Multicyclic compounds and methods of use thereof

ABSTRACT

Provided herein are multicyclic compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or management of various neurological disorders, including but not limited to, psychosis and schizophrenia.

I. CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.14/205,859, filed Mar. 12, 2014, which is a continuation of U.S. patentapplication Ser. No. 13/513,176, filed Jan. 8, 2013, now U.S. Pat. No.8,710,245, which is a § 371 national phase application of InternationalPatent Application No. PCT/US2010/058884, filed Dec. 3, 2010, whichclaims priority to U.S. Provisional Patent Application No. 61/266,880,filed Dec. 4, 2009, the contents of which are hereby incorporated byreference herein in their entirety.

II. FIELD

Provided herein are multicyclic compounds useful for treating variousneurological disorders, including but not limited to, psychosis andschizophrenia, compositions comprising the compounds, and methods of usethereof.

III. BACKGROUND

Central nervous system disorders affect a wide range of the populationwith differing severity. Generally, the major feature of this class ofdisorders includes the significant impairment of cognition or memorythat represents a marked deterioration from a previous level offunctioning.

Schizophrenia is a psychopathic disorder of unknown origin, whichusually appears for the first time in early adulthood and is marked bycharacteristics such as, psychotic symptoms, phasic progression anddevelopment, and/or deterioration in social behavior and professionalcapability. Characteristic psychotic symptoms are disorders of thoughtcontent (e.g., multiple, fragmentary, incoherent, implausible or simplydelusional contents, or ideas of persecution) and of mentality (e.g.,loss of association, flight of imagination, incoherence up toincomprehensibility), as well as disorders of perceptibility (e.g.,hallucinations), emotions (e.g., superficial or inadequate emotions),self-perceptions, intentions, impulses, and/or inter-humanrelationships, and psychomotoric disorders (e.g., catatonia). Othersymptoms are also associated with this disorder. See, e.g., Diagnosticand Statistical Manual of Mental Disorders, 4^(th) Ed., AmericanPsychiatric Association (1997) (DSM-IV™).

Schizophrenia is classified into subgroups. The paranoid type ischaracterized by delusions and hallucinations and absence of thoughtdisorder, disorganized behavior, and affective flattening. Thedisorganized type, which is also named “hebephrenic schizophrenia,” inwhich thought disorder and flat affect are present together. Thecataconic type, in which prominent psychomotor disturbances are evident,and symptoms may include catatonic stupor and waxy flexibility. Theundifferentiated type in which psychotic symptoms are present but thecriteria for paranoid, disorganized, or catatonic types have not beenmet. The symptoms of schizophrenia normally manifest themselves in threebroad categories, i.e., positive, negative and cognitive symptoms.Positive symptoms are those, which represent an “excess” of normalexperiences, such as hallucinations and delusions. Negative symptoms arethose where the patient suffers from a lack of normal experiences, suchas anhedonia and lack of social interaction. The cognitive symptomsrelate to cognitive impairment in schizophrenics, such as lack ofsustained attention and deficits in decision making. The currentantipsychotics may be successful in treating the positive symptoms butfare less well for the negative and cognitive symptoms.

Cognitive impairment includes a decline in cognitive functions orcognitive domains, e.g., working memory, attention and vigilance, verballearning and memory, visual learning and memory, reasoning and problemsolving (e.g., executive function, speed of processing and/or socialcognition). In particular, cognitive impairment may indicate deficits inattention, disorganized thinking, slow thinking, difficulty inunderstanding, poor concentration, impairment of problem solving, poormemory, difficulties in expressing thoughts, and/or difficulties inintegrating thoughts, feelings and behavior, or difficulties inextinction of irrelevant thoughts.

Agitation is a well-recognized behavioral disorder with a range ofsymptoms, including hostility, extreme excitement, poor impulse control,tension and/or uncooperativeness. Agitation is common in the elderly andoften associated with dementia such as those caused by Alzheimer'sdisease, Parkinson's disease, and Huntington's disease, and by diseasesthat affect blood vessels, such as stroke or multi-infarct dementia,which is caused by multiple strokes in the brain. An estimated fivepercent of people aged 65 and older and up to 20 percent of those aged80 and older are affected by dementia; of these sufferers, nearly halfexhibit behavioral disturbances, such as agitation, wandering, andviolent outbursts. Agitated behaviors can also be manifested incognitively intact elderly people and by those with psychiatricdisorders other than dementia.

Dementia is characterized by several cognitive impairments includingsignificant memory deficit and can stand alone, or be an underlyingcharacteristic feature of a variety of diseases, including but notlimited to, Alzheimer's disease, Parkinson's disease, Huntington'sdisease, and multiple sclerosis.

Therefore, there is a great need for effective treatments of variousneurological disorders, including but not limited to, psychosis andschizophrenia.

IV. SUMMARY

Provided herein are compounds of formula (I), or pharmaceuticallyacceptable salts or stereoisomers thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, Y, Z¹, Z², Z³, m, and n aredefined herein elsewhere. The compounds are useful for treating variousdisorders, such as neurological disorders including, but not limited to,psychosis and schizophrenia.

Also provided herein are compositions and dosage forms, comprising acompound provided herein, and one or more pharmaceutically acceptableexcipients. Compositions and dosage forms provided herein may furthercomprise one or more additional active ingredients.

Also provided herein are methods for the treatment, prevention, and/ormanagement of various neurological disorders, including those of thecentral nervous system (CNS) using the compounds and compositionsprovided herein. In one embodiment, provided herein is a method oftreating or managing one or more symptoms of a neurological disorderprovided herein. Such neurological disorders include, but are notlimited to, schizophrenia, schizophrenia spectrum disorder, acuteschizophrenia, chronic schizophrenia, NOS schizophrenia, schizoidpersonality disorder, schizotypal personality disorder, delusionaldisorder, psychosis, psychotic disorder, brief psychotic disorder,shared psychotic disorder, psychotic disorder due to a general medicalcondition, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine),psychoaffective disorder, aggression, delirium, Parkinson's psychosis,excitative psychosis, Tourette's syndrome, organic or NOS psychosis,seizure, agitation, post-traumatic stress disorder, behavior disorder,neurodegenerative disease, Alzheimer's disease, Parkinson's disease,dyskinesias, Huntington's disease, dementia, mood disorder, anxiety,affective disorders (e.g., depression, e.g., major depressive disorderand dysthymia; bipolar disorder, e.g., bipolar depressive disorder;manic disorder; seasonal affective disorder; and attention deficitdisorder (ADD) and attention deficit hyperactivity disorder (ADHD)),obsessive-compulsive disorder, vertigo, epilepsy, pain (e.g.,neuropathic pain, sensitization accompanying neuropathic pain, andinflammatory pain), fibromyalgia, migraine, cognitive impairment,movement disorder, restless leg syndrome (RLS), multiple sclerosis,sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness,jet lag, drowsy side effect of medications, insomnia, substance abuse ordependency (e.g., nicotine, cocaine), addiction, eating disorder, sexualdysfunction, hypertension, emesis, Lesche-Nyhane disease, Wilson'sdisease, autism, Huntington's chorea, and premenstrual dysphoria.

In one embodiment, provided herein is a method of treating, preventing,and/or managing psychosis or schizophrenia. In one embodiment, providedherein is a method of treating or managing one or more symptoms ofpsychosis or schizophrenia. In one embodiment, provided herein is amethod of treating, preventing, and/or managing psychosis orschizophrenia in a subject, such as a mammal, such as, e.g., human,rodent (such as, e.g., mice and rats), cat, dog, non-human primate,among others. In one embodiment, the method comprises contacting acompound provided herein with one or more receptors of the centralnervous system. In one embodiment, the method comprises contacting acell with a compound provided herein. In an exemplary embodiment, thecell is a brain cell, such as, e.g., a neuronal cell or a glial cell.

V. DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as those commonly understood by one of ordinaryskill in the art. In certain embodiments, abbreviations are as definedin J. Org. Chem. 2007, 72, 23A. All publications and patents referred toherein are incorporated by reference herein in their entireties.

A. Definitions

As used in the specification and the accompanying claims, the indefinitearticles “a” and “an” and the definite article “the” include plural aswell as singular referents, unless the context clearly dictatesotherwise.

As used herein, and unless otherwise indicated, the term “alkyl” refersto a linear or branched saturated monovalent hydrocarbon radical,wherein the alkyl may optionally be substituted with one or moresubstituents. In certain embodiments, the alkyl is a linear saturatedmonovalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15(C₁₋₁₅), 1 to 12 (C₁₋₁₂), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbonatoms, or branched saturated monovalent hydrocarbon radical of 3 to 20(C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3 to 6(C₃₋₆) carbon atoms. As used herein, linear C₁₋₆ and branched C₃₋₆ alkylgroups are also referred as “lower alkyl.” Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl (including allisomeric forms, e.g., n-propyl and isopropyl), butyl (including allisomeric forms, e.g., n-butyl, isobutyl, and t-butyl), pentyl (includingall isomeric forms), and hexyl (including all isomeric forms). Forexample, C₁₋₆ alkyl refers to a linear saturated monovalent hydrocarbonradical of 1 to 6 carbon atoms or a branched saturated monovalenthydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, thealkyl is optionally substituted as described herein elsewhere.

As used herein, and unless otherwise specified, the term “alkenyl”refers to a linear or branched monovalent hydrocarbon radical, whichcontains one or more, in one embodiment, one to five, carbon-carbondouble bonds. The alkenyl may be optionally substituted with one or moresubstituents. The term “alkenyl” also encompasses radicals having “cis”and “trans” configurations, or alternatively, “E” and “Z”configurations, as appreciated by those of ordinary skill in the art.For example, C₂₋₆ alkenyl refers to a linear unsaturated monovalenthydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturatedmonovalent hydrocarbon radical of 3 to 6 carbon atoms. In certainembodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 12 (C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2to 6 (C₂₋₆) carbon atoms, or a branched monovalent hydrocarbon radicalof 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀),or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenyl groups include, butare not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl,and 4-methylbutenyl. In certain embodiments, the alkenyl is optionallysubstituted as described herein elsewhere.

As used herein, and unless otherwise specified, the term “alkynyl”refers to a linear or branched monovalent hydrocarbon radical, whichcontains one or more, in one embodiment, one to five, carbon-carbontriple bonds. The alkynyl may be optionally substituted with one or moresubstituents. In certain embodiments, the alkynyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 12(C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branchedmonovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples ofalkynyl groups include, but are not limited to, ethynyl (—C≡CH) andpropargyl (—CH₂C≡CH). For example, C₂₋₆ alkynyl refers to a linearunsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or abranched unsaturated monovalent hydrocarbon radical of 3 to 6 carbonatoms. In certain embodiments, the alkynyl is optionally substituted asdescribed herein elsewhere.

As used herein, and unless otherwise specified, the term “cycloalkyl”refers to a cyclic fully or partially saturated bridged and/ornon-bridged hydrocarbon radical or ring system, which may be optionallysubstituted with one or more substituents. In certain embodiments, thecycloalkyl has from 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 12(C₃₋₁₂), from 3 to 10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms.Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,decalinyl, and adamantyl. In certain embodiments, the cycloalkyl isoptionally substituted as described herein elsewhere.

As used herein, and unless otherwise specified, the term “heteroalkyl”refers to a stable straight or branched chain, or cyclic hydrocarbonradical, or combinations thereof, consisting of the stated number ofcarbon atoms and from one or more, in one embodiment, one to three,heteroatoms selected from the group consisting of O, N, Si, and S, andwherein the nitrogen and sulfur atoms are optionally oxidized and thenitrogen heteroatom can optionally be quaternized. In one embodiment,the heteroatom(s) O, N and S can be placed at any interior position ofthe heteroalkyl group. In one embodiment, the heteroatom Si can beplaced at any position of the heteroalkyl group (e.g., interior orterminal position), including the position at which the alkyl group isattached to the remainder of the molecule. Examples include, but are notlimited to, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatomscan be consecutive, such as, for example, —CH₂—NH—O—CH₃ and—CH₂—O—Si(CH₃)₃. In certain embodiments, the heteroalkyl is optionallysubstituted as described herein elsewhere.

As used herein, and unless otherwise specified, the term “alkoxyl”refers to a stable straight or branched chain, or cyclic hydrocarbonradical, or combinations thereof, consisting of the stated number ofcarbon atoms and from one or more, in one embodiment, one to three, Oatoms. Examples of alkoxyl include, but are not limited to, —O—CH₃,—O—CF₃, —O—CH₂—CH₃, —O—CH₂—CH₂—CH₃, —O—CH—(CH₃)₂, and —O—CH₂—CH₂—O—CH₃.In one embodiment, the alkoxyl is optionally substituted as describedherein elsewhere.

As used herein, and unless otherwise specified, the term “aminoalkyl”refers to a stable straight or branched chain, or cyclic hydrocarbonradical, or combinations thereof, consisting of the stated number ofcarbon atoms and from one or more, in one embodiment, one to three, Natoms. Examples of aminoalkyl include, but are not limited to, —NH—CH₃,—N(CH₃)₂, —NH—CH₂—CH₃, —N(CH₃)—CH₂—CH₃, —NH—CH—(CH₃)₂, —CH₂—CH₂—NH—CH₃,and —CH₂—CH₂—N(CH₃)₂. In one embodiment, the aminoalkyl is optionallysubstituted as described herein elsewhere. In some embodiments, theaminoalkyl is optionally substituted with one or more halo.

As used herein, and unless otherwise specified, the term “aryl” refersto an optionally substituted monocyclic or multicyclic radical or ringsystem that contains at least one aromatic hydrocarbon ring. In certainembodiments, the aryl has from 6 to 20, from 6 to 15, or from 6 to 10ring atoms. Examples of aryl groups include, but are not limited to,phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl,biphenyl, and terphenyl. In certain embodiments, aryl also refers tobicyclic, tricyclic, or tetracyclic carbon rings, where one of the ringsis aromatic and the other(s) of the rings may be saturated, partiallyunsaturated, or aromatic, for example, dihydronaphthyl, indenyl,indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments,aryl may be a bicyclic, tricyclic, or tetracyclic ring system, where atleast one of the rings is aromatic and one or more of the ring(s) is/aresaturated or partially unsaturated containing one or more heteroatomsindependently selected from O, S, and N. In certain embodiments, thearyl is optionally substituted with one or more substituents asdescribed herein elsewhere.

As used herein, and unless otherwise specified, the term “arylalkyl” or“aralkyl” refers to a monovalent alkyl group substituted with aryl.Example of aralkyl includes, but is not limited to, benzyl. In certainembodiments, both alkyl and aryl may be optionally substituted with oneor more substituents as described herein elsewhere.

As used herein, and unless otherwise specified, the term“cycloalkylalkyl” refers to a monovalent alkyl group substituted withcycloalkyl. In certain embodiments, both the alkyl and cycloalkyl may beoptionally substituted with one or more substituents as described hereinelsewhere.

As used herein, and unless otherwise specified, the term “heteroaryl”refers to an optionally substituted monocyclic or multicyclic radical orring system which contains at least one aromatic ring having one or moreheteroatoms independently selected from O, S, and N. In one embodiment,each ring of a heteroaryl group can contain one or two O atoms, one ortwo S atoms, and/or one to four N atoms, provided that the total numberof heteroatoms in each ring is four or less and each ring contains atleast one carbon atom. In certain embodiments, the heteroaryl has from 5to 20, from 5 to 15, or from 5 to 10 ring atoms. In certain embodiments,heteroaryl also refers to bicyclic, tricyclic, or tetracyclic rings,where one of the rings is aromatic having one or more heteroatomsindependently selected from O, S, and N, and the other(s) of the ringsmay be saturated, partially unsaturated, or aromatic and may becarbocyclic or contain one or more heteroatoms independently selectedfrom O, S, and N. Examples of monocyclic heteroaryl groups include, butare not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl,triazinyl, and triazolyl. Examples of bicyclic heteroaryl groupsinclude, but are not limited to, benzofuranyl, benzimidazolyl,benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl,benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl,imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl,isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl,pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl,quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl.Examples of tricyclic heteroaryl groups include, but are not limited to,acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl,phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, theheteroaryl is optionally substituted with one or more substituents asdescribed herein elsewhere.

As used herein, and unless otherwise specified, the term“heterocycloalkyl” or “heterocyclyl” refers to an optionally substitutedmonocyclic or multicyclic radical or ring system which contains at leastone non-aromatic ring having one or more heteroatoms independentlyselected from O, S, and N, and the remaining ring atoms are carbonatoms. In certain embodiments, the heterocyclyl or heterocycloalkylgroup has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4to 7, or from 5 to 6 ring atoms. In certain embodiments, theheterocyclyl or heterocycloalkyl is a monocyclic, bicyclic, tricyclic,or tetracyclic ring system, which may include a fused or bridged ringsystem, and in which the nitrogen or sulfur atoms may be optionallyoxidized, the nitrogen atoms may be optionally quaternized, the ringcarbon atoms may be optionally substituted with oxo, and some rings maybe partially or fully saturated, or aromatic. The heterocycloalkyl orheterocyclyl may be attached to the main structure at a heteroatom or acarbon atom which results in the creation of a stable compound. Examplesinclude, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl,benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl,chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl,dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl,dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl,1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, when the heterocyclyl orheterocycloalkyl ring contains one or more 0, the heterocyclyl orheterocycloalkyl may also be referred to as “cycloalkoxyl.” In certainembodiments, the heterocyclyl or heterocycloalkyl is optionallysubstituted with one or more substituents as described herein elsewhere.

As used herein, and unless otherwise specified, the term “halogen”,“halide” or “halo” refers to fluorine, chlorine, bromine, and iodine.

As used herein, and unless otherwise specified, the term “hydrogen”encompasses proton (¹H), deuterium (²H), tritium (³H), and/or mixturesthereof. In a compound described herein, one or more positions occupiedby hydrogen may be enriched with deuterium and/or tritium. Suchisotopically enriched analogs may be prepared from suitable isotopicallylabeled starting material obtained from a commercial source or preparedusing known literature procedures.

As used herein, and unless otherwise specified, the term “optionallysubstituted” is intended to mean that a group, such as an alkyl,alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl,cycloalkylalkyl, heteroaryl, or heterocyclyl, may be substituted withone or more substituents independently selected from, e.g., (a) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, and heterocyclyl, each optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ¹; and (b) halo, cyano (—CN), nitro (—NO₂), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(e), wherein eachR^(a), R^(b), R^(e), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ¹; or (iii) R^(b) and R^(e) together with the N atom to which they areattached form heteroaryl or heterocyclyl, optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ¹. As used herein, all groups that can be substituted are “optionallysubstituted,” unless otherwise specified.

In one embodiment, each Q¹ is independently selected from the groupconsisting of (a) cyano, halo, and nitro; and (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl.

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic acids, including inorganic acidsand organic acids. Suitable non-toxic acids include inorganic andorganic acids, such as, including but not limited to, acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic, glucorenic,galacturonic, glycidic, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, propionic, phosphoric, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic.

As used herein, and unless otherwise specified, the term “solvate”refers to a compound provided herein or a salt thereof, which furtherincludes a stoichiometric or non-stoichiometric amount of solvent boundby non-covalent intermolecular forces. Where the solvent is water, thesolvate is a hydrate.

As used herein, and unless otherwise specified, the term “stereoisomer”encompasses all enantiomerically/diastereomerically/stereomerically pureand enantiomerically/diastereomerically/stereomerically enrichedcompounds provided herein.

As used herein and unless otherwise specified, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo chiral centers will be substantially free of other diastereomers ofthe compound. A typical stereomerically pure compound comprises greaterthan about 80% by weight of one stereoisomer of the compound and lessthan about 20% by weight of other stereoisomers of the compound, greaterthan about 90% by weight of one stereoisomer of the compound and lessthan about 10% by weight of the other stereoisomers of the compound,greater than about 95% by weight of one stereoisomer of the compound andless than about 5% by weight of the other stereoisomers of the compound,greater than about 97% by weight of one stereoisomer of the compound andless than about 3% by weight of the other stereoisomers of the compound,or greater than about 99% by weight of one stereoisomer of the compoundand less than about 1% by weight of the other stereoisomers of thecompound.

As used herein and unless otherwise indicated, the term “stereomericallyenriched” means a composition that comprises greater than about 55% byweight of one stereoisomer of a compound, greater than about 60% byweight of one stereoisomer of a compound, greater than about 70% byweight, or greater than about 80% by weight of one stereoisomer of acompound.

As used herein, and unless otherwise indicated, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one chiral center. Similarly, the term “enantiomericallyenriched” means a stereomerically enriched composition of a compoundhaving one chiral center.

In certain embodiments, as used herein, and unless otherwise specified,“optically active” and “enantiomerically active” refer to a collectionof molecules, which has an enantiomeric excess or diastereomeric excessof no less than about 50%, no less than about 70%, no less than about80%, no less than about 90%, no less than about 91%, no less than about92%, no less than about 93%, no less than about 94%, no less than about95%, no less than about 96%, no less than about 97%, no less than about98%, no less than about 99%, no less than about 99.5%, or no less thanabout 99.8%. In certain embodiments, the compound comprises about 95% ormore of the desired enantiomer or diastereomer and about 5% or less ofthe less preferred enantiomer or diastereomer based on the total weightof the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

As used herein, and unless otherwise specified, the Willi “about” or“approximately” means an acceptable error for a particular value asdetermined by one of ordinary skill in the art, which depends in part onhow the value is measured or determined. In certain embodiments, theterm “about” or “approximately” means within 1, 2, 3, or 4 standarddeviations. In certain embodiments, the term “about” or “approximately”means within 50%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%,2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable carrier,” “pharmaceutically acceptableexcipient,” “physiologically acceptable carrier,” or “physiologicallyacceptable excipient” refers to a pharmaceutically-acceptable material,composition, or vehicle, such as a liquid or solid filler, diluent,solvent, or encapsulating material. In one embodiment, each component is“pharmaceutically acceptable” in the sense of being compatible with theother ingredients of a pharmaceutical formulation, and suitable for usein contact with the tissue or organ of humans and animals withoutexcessive toxicity, irritation, allergic response, immunogenicity, orother problems or complications, commensurate with a reasonablebenefit/risk ratio. See, Remington: The Science and Practice ofPharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia,Pa., 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe etal., Eds., The Pharmaceutical Press and the American PharmaceuticalAssociation: 2005; and Handbook of Pharmaceutical Additives, 3rdEdition, Ash and Ash Eds., Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed.,CRC Press LLC: Boca Raton, Fla., 2009.

As used herein, and unless otherwise specified, the terms “activeingredient” and “active substance” refer to a compound, which isadministered, alone or in combination with one or more pharmaceuticallyacceptable excipients, to a subject for treating, preventing, orameliorating one or more symptoms of a condition, disorder, or disease.As used herein, “active ingredient” and “active substance” may be anoptically active isomer of a compound described herein.

As used herein, and unless otherwise specified, the terms “drug” and“therapeutic agent” refer to a compound, or a pharmaceutical compositionthereof, which is administered to a subject for treating, preventing,managing, or ameliorating one or more symptoms of a condition, disorder,or disease.

As used herein, and unless otherwise indicated, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In one embodiment, such symptoms are those known toa person of skill in the art to be associated with the disease ordisorder being treated. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a subject with such a disease or disorder. In someembodiments, the terms refer to the administration of a compoundprovided herein, with or without other additional active agent, afterthe onset of symptoms of the particular disease.

As used herein, and unless otherwise indicated, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms associated with the disease or disorder. In one embodiment,such symptoms are those known to a person of skill in the art to beassociated with the disease or disorder being prevented. In certainembodiments, the terms refer to the treatment with or administration ofa compound provided herein, with or without other additional activecompound, prior to the onset of symptoms, particularly to patients atrisk of disease or disorders provided herein. The terms encompass theinhibition or reduction of a symptom of the particular disease. Patientswith familial history of a disease in particular are candidates forpreventive regimens in certain embodiments. In addition, patients whohave a history of recurring symptoms are also potential candidates forthe prevention. In this regard, the term “prevention” may beinterchangeably used with the term “prophylactic treatment.”

As used herein, and unless otherwise specified, the terms “manage,”“managing,” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms associated with the disease or disorder. In oneembodiment, such symptoms are those known to a person of skill in theart to be associated with the disease or disorder being managed. Often,the beneficial effects that a subject derives from a prophylactic and/ortherapeutic agent do not result in a cure of the disease or disorder. Inthis regard, the term “managing” encompasses treating a patient who hadsuffered from the particular disease in an attempt to prevent orminimize the recurrence of the disease.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease or disorder, or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other agents, which provides a prophylacticbenefit in the prevention of the disease. The term “prophylacticallyeffective amount” can encompass an amount that improves overallprophylaxis or enhances the prophylactic efficacy of anotherprophylactic agent.

As used herein, and unless otherwise specified, the term “subject” isdefined herein to include animals such as mammals, including, but notlimited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,cats, rabbits, rats, mice and the like. In specific embodiments, thesubject is a human.

As used herein, and unless otherwise specified, the term “neurologicaldisorder” refers to any condition of the central or peripheral nervoussystem of a mammal. The term “neurological disorder” includes, but isnot limited to, neurodegenerative diseases (e.g., Alzheimer's disease,Parkinson's disease and amyotrophic lateral sclerosis), neuropsychiatricdiseases (e.g., schizophrenia and anxieties, such as general anxietydisorder), and affective disorders (e.g., depression, bipolar disorder,manic conditions, and attention deficit disorder). Exemplaryneurological disorders include, but are not limited to, MLS (cerebellarataxia), Huntington's disease, Down syndrome, multi-infarct dementia,status epilecticus, contusive injuries (e.g., spinal cord injury andhead injury), viral infection induced neurodegeneration, (e.g., AIDS,encephalopathies), epilepsy, benign forgetfulness, closed head injury,sleep disorders, major depressive disorder, dysthymia, seasonalaffective disorder, dementias, movement disorders, psychosis,alcoholism, post-traumatic stress disorder, and the like. “Neurologicaldisorder” also includes any condition associated with the disorder. Forinstance, a method of treating a neurodegenerative disorder includesmethods of treating loss of memory and/or loss of cognition associatedwith a neurodegenerative disorder. An exemplary method would alsoinclude treating or preventing loss of neuronal function characteristicof neurodegenerative disorder. “Neurological disorder” also includes anydisease or condition that is implicated, at least in part, in monoamine(e.g., norepinephrine) signaling pathways (e.g., cardiovasculardisease).

As used herein, and unless otherwise specified, the terms “psychosis,”“schizophrenia,” “obsessive-compulsive disorder,” “substance abuse,”“anxiety,” “eating disorders,” “migraine,” and other CNS or neurologicaldisorders described herein elsewhere are used herein in a mannerconsistent with their accepted meanings in the art. See, e.g.,Diagnostic and Statistical Manual of Mental Disorders, 4^(th) Ed.,American Psychiatric Association (1997) (DSM-IV™).

As used herein, and unless otherwise specified, the term “seizure”refers to a neurological disorder and may be used interchangeably with“convulsion,” although there are many types of seizure, some of whichhave subtle or mild symptoms instead of convulsions. In one embodiment,the term “seizure” as used herein is intended to encompass “convulsion.”In some embodiments, seizures may be caused by disorganized and suddenelectrical activity in the brain. In some embodiments, convulsions are arapid and uncontrollable shaking during which the muscles contract andrelax repeatedly. Unless otherwise specified, the terms “convulsion” and“seizure” are used herein in accordance with the accepted meanings asfound in the Diagnostic and Statistical Manual of Mental Disorders,4^(th) Ed., American Psychiatric Association (1997) (DSM-IV™).

As used herein, and unless otherwise specified, the term “affectivedisorder” includes depression, attention deficit disorder, attentiondeficit disorder with hyperactivity, bipolar disorder, and manicdisorder, and the like.

As used herein, and unless otherwise specified, the term “depression”includes all forms of depression, including, but not limited to, majordepressive disorder (MDD) or unipolar depressive disorder, dysthymia,seasonal affective disorder (SAD), and bipolar depressive disorder.“Major depressive disorder” is used herein interchangeably with“unipolar depression”, “unipolar depressive disorder”, and “majordepression.” “Depression” may also include any condition commonlyassociated with depression, such as all forms of fatigue (e.g., chronicfatigue syndrome) and cognitive deficits.

Unless otherwise specified, the terms “bipolar disorder” and “manicdisorder” are used herein in accordance with the accepted meanings asfound in the Diagnostic and Statistical Manual of Mental Disorders,4^(th) Ed., American Psychiatric Association (1997) (DSM-IV™).

Unless otherwise specified, the terms “attention deficit disorder”(ADD), and “attention deficit disorder with hyperactivity” (ADDH) or“attention deficit hyperactivity disorder” (ADHD), are used herein inaccordance with the accepted meanings as found in the Diagnostic andStatistical Manual of Mental Disorders, 4^(th) Ed., American PsychiatricAssociation (1997) (DSM-IV™).

As used herein, and unless otherwise specified, the term “pain” refersto an unpleasant sensory and emotional experience. Unless otherwisespecified, the term “pain,” as used herein, refers to all categories ofpain, including pain that is described in terms of stimulus or nerveresponse, e.g., somatic pain (normal nerve response to a noxiousstimulus) and neuropathic pain (abnormal response of a injured oraltered sensory pathway, often without clear noxious input); pain thatis categorized temporally, e.g., chronic pain and acute pain; pain thatis categorized in terms of its severity, e.g., mild, moderate, orsevere; and pain that is a symptom or a result of a disease state orsyndrome, e.g., inflammatory pain, cancer pain, AIDS pain, arthropathy,migraine, trigeminal neuralgia, cardiac ischaemia, and diabeticperipheral neuropathic pain (See, e.g., Harrison's Principles ofInternal Medicine, pp. 93-98 (Wilson et al., eds., 12th ed. 1991);Williams et al., J. of Med. Chen. 42: 1481-1485 (1999), herein eachincorporated by reference in their entirety). “Pain” is also meant toinclude mixed etiology pain, dual mechanism pain, allodynia, causalgia,central pain, hyperesthesia, hyperpathia, dysesthesia, and hyperalgesia.In one embodiment, the team “pain” includes pain resulting fromdysfunction of the nervous system: organic pain states that shareclinical features of neuropathic pain and possible commonpathophysiology mechanisms, but are not initiated by an identifiablelesion in any part of the nervous system.

Unless otherwise specified, the term “somatic pain,” as used herein,refers to a normal nerve response to a noxious stimulus such as injuryor illness, e.g., trauma, burn, infection, inflammation, or diseaseprocess such as cancer, and includes both cutaneous pain (e.g., skin,muscle or joint derived) and visceral pain (e.g., organ derived).

Unless otherwise specified, the term “neuropathic pain,” as used herein,refers to a heterogeneous group of neurological conditions that resultfrom damage to the nervous system. The term also refers to painresulting from injury to or dysfunctions of peripheral and/or centralsensory pathways, and from dysfunctions of the nervous system, where thepain often occurs or persists without an obvious noxious input. Thisincludes pain related to peripheral neuropathies as well as centralneuropathic pain. Common types of peripheral neuropathic pain includediabetic neuropathy (also called diabetic peripheral neuropathic pain,or DN, DPN, or DPNP), post-herpetic neuralgia (PHN), and trigeminalneuralgia (TGN). Central neuropathic pain, involving damage to the brainor spinal cord, can occur following stroke, spinal cord injury, and as aresult of multiple sclerosis, and is also encompassed by the term. Othertypes of pain that are meant to be included in the definition ofneuropathic pain include, but are not limited to, neuropathic cancerpain, HIV/AIDS induced pain, phantom limb pain, and complex regionalpain syndrome. Unless otherwise specified, the term also encompasses thecommon clinical features of neuropathic pain including, but not limitedto, sensory loss, allodynia (non-noxious stimuli produce pain),hyperalgesia and hyperpathia (delayed perception, summation, and painfulafter sensation). Pain is often a combination of nociceptive andneuropathic types, for example, mechanical spinal pain and radiculopathyor myelopathy.

As used herein, and unless otherwise specified, the term “acute pain”refers to the normal, predicted physiological response to a noxiouschemical, thermal or mechanical stimulus typically associated withinvasive procedures, trauma and disease. It is generally time-limited,and may be viewed as an appropriate response to a stimulus thatthreatens and/or produces tissue injury. The term also refers to painwhich is marked by short duration or sudden onset.

As used herein, and unless otherwise specified, the term “chronic pain”encompasses the pain occurring in a wide range of disorders, forexample, trauma, malignancies and chronic inflammatory diseases such asrheumatoid arthritis. Chronic pain may last more than about six months.In addition, the intensity of chronic pain may be disproportionate tothe intensity of the noxious stimulus or underlying process. The termsalso refers to pain associated with a chronic disorder, or pain thatpersists beyond resolution of an underlying disorder or healing of aninjury, and that is often more intense than the underlying process wouldpredict. It may be subject to frequent recurrence.

As used herein, and unless otherwise specified, the term “inflammatorypain” is pain in response to tissue injury and the resultinginflammatory process. Inflammatory pain is adaptive in that it elicitsphysiologic responses that promote healing. However, inflammation mayalso affect neuronal function. Inflammatory mediators, including PGE₂induced by the COX2 enzyme, bradykinins, and other substances, bind toreceptors on pain-transmitting neurons and alter their function,increasing their excitability and thus increasing pain sensation. Muchchronic pain has an inflammatory component. The term also refers to painwhich is produced as a symptom or a result of inflammation or an immunesystem disorder.

As used herein, and unless otherwise specified, the term “visceral pain”refers to pain which is located in an internal organ.

As used herein, and unless otherwise specified, the term “mixed etiologypain” refers to pain that contains both inflammatory and neuropathiccomponents.

As used herein, and unless otherwise specified, the term “dual mechanismpain” refers to pain that is amplified and maintained by both peripheraland central sensitization.

As used herein, and unless otherwise specified, the term “causalgia”refers to a syndrome of sustained burning, allodynia, and hyperpathiaafter a traumatic nerve lesion, often combined with vasomotor andsudomotor dysfunction and later trophic changes. As used herein, andunless otherwise specified, the term “central pain” refers to paininitiated by a primary lesion or dysfunction in the central nervoussystem.

As used herein, and unless otherwise specified, the term “hyperesthesia”refers to increased sensitivity to stimulation, excluding the specialsenses.

As used herein, and unless otherwise specified, the term “hyperpathia”refers to a painful syndrome characterized by an abnormally painfulreaction to a stimulus, especially a repetitive stimulus, as well as anincreased threshold. It may occur with allodynia, hyperesthesia,hyperalgesia, or dysesthesia.

As used herein, and unless otherwise specified, the term “dysesthesia”refers to an unpleasant abnormal sensation, whether spontaneous orevoked. In certain embodiments, dysesthesia include hyperalgesia andallodynia.

As used herein, and unless otherwise specified, the term “hyperalgesia”refers to an increased response to a stimulus that is normally painful.It reflects increased pain on suprathreshold stimulation.

As used herein, and unless otherwise specified, the term “allodynia”refers to pain due to a stimulus that does not normally provoke pain.

As used herein, and unless otherwise specified, the term “diabeticperipheral neuropathic pain” (DPNP), also called diabetic neuropathy, DNor diabetic peripheral neuropathy), refers to chronic pain caused byneuropathy associated with diabetes mellitus. The classic presentationof DPNP is pain or tingling in the feet that can be described not onlyas “burning” or “shooting” but also as severe aching pain. Lesscommonly, patients may describe the pain as itching, tearing, or like atoothache. The pain may be accompanied by allodynia and hyperalgesia andan absence of symptoms, such as numbness.

As used herein, and unless otherwise specified, the term “post-herpeticneuralgia”, also called “postherpetic neuralgia” (PHN), refers to apainful condition affecting nerve fibers and skin. Without being limitedby a particular theory, it is a complication of shingles, a secondoutbreak of the varicella zoster virus (VZV), which initially causeschickenpox.

As used herein, and unless otherwise specified, the term “neuropathiccancer pain” refers to peripheral neuropathic pain as a result ofcancer, and can be caused directly by infiltration or compression of anerve by a tumor, or indirectly by cancer treatments such as radiationtherapy and chemotherapy (chemotherapy-induced neuropathy).

As used herein, and unless otherwise specified, the term “HIV/AIDSperipheral neuropathy” or “HIV/AIDS related neuropathy” refers toperipheral neuropathy caused by HIV/AIDS, such as acute or chronicinflammatory demyelinating neuropathy (AIDP and CIDP, respectively), aswell as peripheral neuropathy resulting as a side effect of drugs usedto treat HIV/AIDS.

As used herein, and unless otherwise specified, the term “phantom limbpain” refers to pain appearing to come from where an amputated limb usedto be. Phantom limb pain can also occur in limbs following paralysis(e.g., following spinal cord injury). “Phantom limb pain” is usuallychronic in nature.

As used herein, and unless otherwise specified, the term “trigeminalneuralgia” (TN) refers to a disorder of the fifth cranial (trigeminal)nerve that causes episodes of intense, stabbing, electric-shock-likepain in the areas of the face where the branches of the nerve aredistributed (lips, eyes, nose, scalp, forehead, upper jaw, and lowerjaw). It is also known as the “suicide disease”.

As used herein, and unless otherwise specified, the term “complexregional pain syndrome” (CRPS), formerly known as “reflex sympatheticdystrophy” (RSD), refers to a chronic pain condition whose key symptomis continuous, intense pain out of proportion to the severity of theinjury, which gets worse rather than better over time. The termencompasses type 1 CRPS, which includes conditions caused by tissueinjury other than peripheral nerve, and type 2 CRPS, in which thesyndrome is provoked by major nerve injury, and is sometimes calledcausalgia.

As used herein, and unless otherwise specified, the term “fibromyalgia”refers to a chronic condition characterized by diffuse or specificmuscle, joint, or bone pain, along with fatigue and a range of othersymptoms. Previously, fibromyalgia was known by other names such asfibrositis, chronic muscle pain syndrome, psychogenic rheumatism andtension myalgias.

B. Compounds

In one embodiment, provided herein is a compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

one of X and Y is O, and the other is CH₂; or both X and Y are CH₂;

one of Z¹, Z², and Z³ is S; and (i) two of Z¹, Z², and Z³ are C; or (ii)one of Z¹, Z², and Z³ is C and one of Z¹, Z², and Z³ is N;

R¹ and R² are each independently (i) hydrogen, alkyl, alkoxyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, oraralkyl, each of which is optionally substituted; or (ii) —(CH₂)_(p)—R⁸,wherein R⁸ is SO₂alkyl or SO₂aryl, each of which is optionallysubstituted; or (iii) R¹ and R² together with the nitrogen atom to whichthey are attached form an optionally substituted heterocyclyl orheteroaryl;

R³ and R⁴ are each independently (i) hydrogen, alkyl, alkoxyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, oraralkyl, each of which is optionally substituted; or (ii) —(CH₂)_(p)—R⁹,wherein R⁹ is CF₃, CN, nitro, amino, hydroxyl, or cycloalkoxyl, each ofwhich is optionally substituted; or (iii) R³ and R⁴ together with thecarbon atom to which they are attached form an optionally substitutedcycloalkyl or heterocyclyl; or (iv) R³ and R¹ together with the atoms towhich they are attached form an optionally substituted heterocyclyl, andR⁴ is (i) or (ii); or (v) R³ and R⁴ are combined together to form adouble bond and together with R¹ and/or R² and the atoms to which theyare attached form an optionally substituted heteroaryl (e.g., imidazolylor thiazolyl);

R⁵ is (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which isoptionally substituted; or (ii) —(CH₂)_(p)—R¹⁰, wherein R¹⁰ is CF₃, CN,nitro, amino, hydroxyl, or cycloalkoxyl, each of which is optionallysubstituted; or (iii) R⁵ and R¹ together with the atoms to which theyare attached form an optionally substituted heterocyclyl;

R⁶ and R⁷ are each independently (i) hydrogen, halo, alkyl, alkoxyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, oraralkyl, each of which is optionally substituted; or (ii)—(CH₂)_(p)—R¹¹, wherein R¹¹ is CF₃, CN, nitro, amino, hydroxyl,cycloalkoxyl, heteroaryl, or heterocyclyl, each of which is optionallysubstituted; or (iii) R⁶ and R⁷ together with the atoms to which theyare attached form an optionally substituted aryl, heteroaryl, cycloalkylor heterocyclyl ring; with the proviso that when one of Z¹, Z², and Z³is N, R⁷ is absent;

m is 0, 1, or 2;

n is 0, 1, or 2; and

each occurrence of p is independently 0, 1, or 2.

In one embodiment, provided herein is a compound of formula (I), asdefined herein elsewhere, or a pharmaceutically acceptable salt orstereoisomer thereof, wherein:

one of X and Y is O, and the other is CH₂; or both X and Y are CH₂;

two of Z¹, Z², and Z³ are C, and one of Z¹, Z², and Z³ is S;

R¹ and R² are each independently (i) hydrogen, alkyl, alkoxyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, oraralkyl, each of which is optionally substituted; or (ii) —(CH₂)_(p)—R⁸,wherein R⁸ is SO₂alkyl or SO₂aryl, each of which is optionallysubstituted; or (iii) R¹ and R² together with the nitrogen atom to whichthey are attached form an optionally substituted heterocyclyl orheteroaryl;

R³ and R⁴ are each independently (i) hydrogen, alkyl, alkoxyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, oraralkyl, each of which is optionally substituted; or (ii) —(CH₂)_(p)—R⁹,wherein R⁹ is CF₃, CN, nitro, amino, hydroxyl, or cycloalkoxyl, each ofwhich is optionally substituted; or (iii) R³ and R⁴ together with thecarbon atom to which they are attached form an optionally substitutedcycloalkyl or heterocyclyl; or (iv) R³ and R¹ together with the atoms towhich they are attached form an optionally substituted heterocyclyl, andR⁴ is (i) or (ii); or (v) R³ and R⁴ are combined together to form adouble bond and together with R¹ and/or R² and the atoms to which theyare attached form an optionally substituted heteroaryl (e.g., imidazolylor thiazolyl);

R⁵ is (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which isoptionally substituted; or (ii) —(CH₂)_(p)—R¹⁰, wherein R¹⁰ is CF₃, CN,nitro, amino, hydroxyl, or cycloalkoxyl, each of which is optionallysubstituted; or (iii) R⁵ and R¹ together with the atoms to which theyare attached form an optionally substituted heterocyclyl;

R⁶ and R⁷ are each independently (i) hydrogen, halo, alkyl, alkoxyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, oraralkyl, each of which is optionally substituted; or (ii)—(CH₂)_(p)—R¹¹, wherein R¹¹ is CF₃, CN, nitro, amino, hydroxyl,cycloalkoxyl, heteroaryl, or heterocyclyl, each of which is optionallysubstituted; or (iii) R⁶ and R⁷ together with the atoms to which theyare attached form an optionally substituted aryl, heteroaryl, cycloalkylor heterocyclyl ring;

m is 0, 1, or 2;

n is 0, 1, or 2; and

each occurrence of p is independently 0, 1, or 2.

In one embodiment, X is O and Y is CH₂. In one embodiment, X is CH₂ andY is O. In one embodiment, both X and Y are CH₂.

In one embodiment, Z¹ is S. In one embodiment, Z² is S. In oneembodiment, Z³ is S. In one embodiment, Z¹ and Z² are C, and Z³ is S. Inone embodiment, Z¹ and Z³ are C, and Z² is S. In one embodiment, Z² andZ³ are C, and Z¹ is S. In one embodiment, Z¹ is N, Z² is C, and Z³ is S.In one embodiment, Z¹ is C, Z² is N, and Z³ is S. In one embodiment, Z¹is N, Z² is S, and Z³ is C. In one embodiment, Z¹ is C, Z² is S, and Z³is N. In one embodiment, Z¹ is S, Z² is N, and Z³ is C. In oneembodiment, Z¹ is S, Z² is C, and Z³ is N. In one embodiment, when oneof Z¹, Z², and Z³ is N, R⁷ is absent and R⁶ substitutes a carbon ringatom.

In one embodiment, R¹ is hydrogen. In one embodiment, R¹ is optionallysubstituted alkyl. In one embodiment, R¹ is alkyl. In one embodiment, R¹is optionally substituted alkoxyl. In one embodiment, R¹ is alkoxyl. Inone embodiment, R¹ is optionally substituted aminoalkyl. In oneembodiment, R¹ is aminoalkyl. In one embodiment, R¹ is optionallysubstituted alkenyl. In one embodiment, R¹ is alkenyl. In oneembodiment, R¹ is optionally substituted alkynyl. In one embodiment, R¹is alkynyl. In one embodiment, R¹ is optionally substituted cycloalkyl.In one embodiment, R¹ is cycloalkyl. In one embodiment, R¹ is optionallysubstituted cycloalkylalkyl. In one embodiment, R¹ is cycloalkylalkyl.In one embodiment, R¹ is optionally substituted aryl. In one embodiment,R¹ is aryl. In one embodiment, R¹ is optionally substituted aralkyl. Inone embodiment, R¹ is aralkyl. In one embodiment, R¹ is—(CH₂)_(p)—SO₂alkyl, wherein the alkyl is optionally substituted. In oneembodiment, R¹ is —(CH₂)_(p)—SO₂alkyl. In one embodiment, R¹ is—(CH₂)_(p)—SO₂aryl, wherein the aryl is optionally substituted. In oneembodiment, R¹ is —(CH₂)_(p)—SO₂aryl. In one embodiment, R¹ is C₁-C₄alkyl optionally substituted with —SO₂alkyl or —SO₂aryl, each of whichis further optionally substituted. In one embodiment, R¹ is C₁-C₄ alkyloptionally substituted with —SO₂alkyl or —SO₂aryl. In one embodiment,the alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, and cycloalkyl areoptionally substituted with one or more halo.

In one embodiment, R² is hydrogen. In one embodiment, R² is optionallysubstituted alkyl. In one embodiment, R² is alkyl. In one embodiment, R²is optionally substituted alkoxyl. In one embodiment, R² is alkoxyl. Inone embodiment, R² is optionally substituted aminoalkyl. In oneembodiment, R² is aminoalkyl. In one embodiment, R² is optionallysubstituted alkenyl. In one embodiment, R² is alkenyl. In oneembodiment, R² is optionally substituted alkynyl. In one embodiment, R²is alkynyl. In one embodiment, R² is optionally substituted cycloalkyl.In one embodiment, R² is cycloalkyl. In one embodiment, R² is optionallysubstituted cycloalkylalkyl. In one embodiment, R² is cycloalkylalkyl.In one embodiment, R² is optionally substituted aryl. In one embodiment,R² is aryl. In one embodiment, R² is optionally substituted aralkyl. Inone embodiment, R² is aralkyl. In one embodiment, R² is—(CH₂)_(p)—SO₂alkyl, wherein the alkyl is optionally substituted. In oneembodiment, R² is —(CH₂)_(p)—SO₂alkyl. In one embodiment, R² is—(CH₂)_(p)—SO₂aryl, wherein the aryl is optionally substituted. In oneembodiment, R² is —(CH₂)_(p)—SO₂aryl. In one embodiment, R² is C₁-C₄alkyl optionally substituted with —SO₂alkyl or —SO₂aryl, each of whichis further optionally substituted. In one embodiment, R² is C₁-C₄ alkyloptionally substituted with —SO₂alkyl or —SO₂aryl. In one embodiment,the alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, and cycloalkyl areoptionally substituted with one or more halo.

In one embodiment, R¹ and R² together with the nitrogen atom to whichthey are attached form an optionally substituted heterocyclyl. In oneembodiment, R¹ and R² together with the nitrogen atom to which they areattached form a heterocyclyl. In one embodiment, R¹ and R² together withthe nitrogen atom to which they are attached form an optionallysubstituted heteroaryl. In one embodiment, R¹ and R² together with thenitrogen atom to which they are attached form a heteroaryl.

In one embodiment, R³ and R⁴ are each independently (i) hydrogen, alkyl,alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl, each of which is optionally substituted; or (ii)—(CH₂)_(p)—R⁹, wherein R⁹ is CF₃, CN, nitro, amino, hydroxyl, orcycloalkoxyl, each of which is optionally substituted; or (iii) R³ andR⁴ together with the carbon atom to which they are attached form anoptionally substituted cycloalkyl or heterocyclyl; or (iv) R³ and R¹together with the atoms to which they are attached form an optionallysubstituted heterocyclyl, and R⁴ is (i) or (ii); or (v) R³ and R⁴ arecombined together to form a double bond and together with R¹ and theatoms to which they are attached form an optionally substitutedheteroaryl (e.g., imidazolyl).

In one embodiment, R³ is hydrogen. In one embodiment, R³ is optionallysubstituted alkyl. In one embodiment, R³ is alkyl. In one embodiment, R³is optionally substituted alkoxyl. In one embodiment, R³ is alkoxyl. Inone embodiment, R³ is optionally substituted aminoalkyl. In oneembodiment, R³ is aminoalkyl. In one embodiment, R³ is optionallysubstituted alkenyl. In one embodiment, R³ is alkenyl. In oneembodiment, R³ is optionally substituted alkynyl. In one embodiment, R³is alkynyl. In one embodiment, R³ is optionally substituted cycloalkyl.In one embodiment, R³ is cycloalkyl. In one embodiment, R³ is optionallysubstituted cycloalkylalkyl. In one embodiment, R³ is cycloalkylalkyl.In one embodiment, R³ is optionally substituted aryl. In one embodiment,R³ is aryl. In one embodiment, R³ is optionally substituted aralkyl. Inone embodiment, R³ is aralkyl. In one embodiment, R³ is —(CH₂)_(p)—CF₃.In one embodiment, R³ is —(CH₂)_(p)—CN. In one embodiment, R³ is—(CH₂)_(p)-nitro. In one embodiment, R³ is —(CH₂)_(p)-amino, wherein theamino is optionally substituted. In one embodiment, R³ is—(CH₂)_(p)-amino. In one embodiment, R³ is —(CH₂)_(p)-hydroxyl, whereinthe hydroxyl is optionally substituted. In one embodiment, R³ is—(CH₂)_(p)-hydroxyl. In one embodiment, R³ is —(CH₂)_(p)-cycloalkoxyl,wherein the cycloalkoxyl is optionally substituted. In one embodiment,R³ is —(CH₂)_(p)-cycloalkoxyl. In one embodiment, R³ is C₁-C₄ alkyloptionally substituted with CF₃, CN, nitro, amino, hydroxyl, orcycloalkoxyl, each of which is further optionally substituted. In oneembodiment, R³ is C₁-C₄ alkyl optionally substituted with CF₃, CN,nitro, amino, hydroxyl, or cycloalkoxyl. In one embodiment, the alkyl,alkoxyl, aminoalkyl, alkenyl, alkynyl, and cycloalkyl are optionallysubstituted with one or more halo.

In one embodiment, R⁴ is hydrogen. In one embodiment, R⁴ is optionallysubstituted alkyl. In one embodiment, R⁴ is alkyl. In one embodiment, R⁴is optionally substituted alkoxyl. In one embodiment, R⁴ is alkoxyl. Inone embodiment, R⁴ is optionally substituted aminoalkyl. In oneembodiment, R⁴ is aminoalkyl. In one embodiment, R⁴ is optionallysubstituted alkenyl. In one embodiment, R⁴ is alkenyl. In oneembodiment, R⁴ is optionally substituted alkynyl. In one embodiment, R⁴is alkynyl. In one embodiment, R⁴ is optionally substituted cycloalkyl.In one embodiment, R⁴ is cycloalkyl. In one embodiment, R⁴ is optionallysubstituted cycloalkylalkyl. In one embodiment, R⁴ is cycloalkylalkyl.In one embodiment, R⁴ is optionally substituted aryl. In one embodiment,R⁴ is aryl. In one embodiment, R⁴ is optionally substituted aralkyl. Inone embodiment, R⁴ is aralkyl. In one embodiment, R⁴ is —(CH₂)_(p)—CF₃.In one embodiment, R⁴ is —(CH₂)_(p)—CN. In one embodiment, R⁴ is—(CH₂)_(p)-nitro. In one embodiment, R⁴ is —(CH₂)_(p)-amino, wherein theamino is optionally substituted. In one embodiment, R⁴ is—(CH₂)_(p)-amino. In one embodiment, R⁴ is —(CH₂)-hydroxyl, wherein thehydroxyl is optionally substituted. In one embodiment, R⁴ is—(CH₂)-hydroxyl. In one embodiment, R⁴ is —(CH₂)_(p)-cycloalkoxyl,wherein the cycloalkoxyl is optionally substituted. In one embodiment,R⁴ is —(CH₂)_(p)-cycloalkoxyl. In one embodiment, R⁴ is C₁-C₄ alkyloptionally substituted with CF₃, CN, nitro, amino, hydroxyl, orcycloalkoxyl, each of which is further optionally substituted. In oneembodiment, R⁴ is C₁-C₄ alkyl optionally substituted with CF₃, CN,nitro, amino, hydroxyl, or cycloalkoxyl. In one embodiment, the alkyl,alkoxyl, aminoalkyl, alkenyl, alkynyl, and cycloalkyl are optionallysubstituted with one or more halo.

In one embodiment, R³ and R⁴ together with the carbon atom to which theyare attached form an optionally substituted cycloalkyl. In oneembodiment, R³ and R⁴ together with the carbon atom to which they areattached form a cycloalkyl. In one embodiment, R³ and R⁴ together withthe carbon atom to which they are attached form an optionallysubstituted heterocyclyl. In one embodiment, R³ and R⁴ together with thecarbon atom to which they are attached form a heterocyclyl.

In one embodiment, R³ and R¹ together with the atoms to which they areattached form an optionally substituted heterocyclyl, and R⁴ is (i)hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, or aralkyl, each of which is optionallysubstituted; or (ii) —(CH₂)—R⁹, wherein R⁹ is CF₃, CN, nitro, amino,hydroxyl, or cycloalkoxyl, each of which is optionally substituted. Inone embodiment, R³ and R¹ together with the atoms to which they areattached form a heterocyclyl, and R⁴ is (i) hydrogen, alkyl, alkoxyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, oraralkyl; or (ii) —(CH₂)—R⁹, wherein R⁹ is CF₃, CN, nitro, amino,hydroxyl, or cycloalkoxyl.

In one embodiment, R³ and R⁴ are combined together to form a double bondand together with R¹ and the atoms to which they are attached form anoptionally substituted heteroaryl (e.g., imidazole). A skilled personwill understand that when R³ and R⁴ are combined together to faun adouble bond and together with R¹ and the atoms to which they areattached form an optionally substituted heteroaryl, this embodimentcould also be described as: one of R³ and R⁴ is absent and the other ofR³ and R⁴ together with R¹ and the atoms to which they are attached forman optionally substituted heteroaryl (e.g., imidazole), which issubstituted by R² (e.g., substituent on ring nitrogen atom). In oneembodiment, R³ and R⁴ are combined together to form a double bond andtogether with R¹ and the atoms to which they are attached form aheteroaryl. Examples of the heteroaryl include, but are not limited to,imidazolyl, pyrrolyl, benzimidazolyl, or indazolyl. In some embodiments,R¹ and R² are also combined to form a double bond and together with R³and R⁴ and the atoms to which they are attached form an optionallysubstituted heteroaryl (e.g., thiazole). A skilled person willunderstand that when R¹ and R² are also combined together to form adouble bond and together with R³ and R⁴ and the atoms to which they areattached form an optionally substituted heteroaryl, this embodimentcould also be described as: one of R³ and R⁴ is absent and one of R¹ andR² is absent, and the other of R³ and R⁴ together with the other of R¹and R² and the atoms to which they are attached form an optionallysubstituted heteroaryl (e.g., thiazole). In some embodiments, R¹ and R²are also combined to form a double bond and together with R³ and R⁴ andthe atoms to which they are attached form a heteroaryl. Examples of theheteroaryl include, but are not limited to, oxazolyl, isoxazolyl,thiazolyl, pyridyl, or benzoxazolyl. In one embodiment, R¹, R², R³, andR⁴ are combined together with the atoms to which they are attached forman optionally substituted heteroaryl (e.g., imidazole or thiazole).

In one embodiment, R⁵ is hydrogen. In one embodiment, R⁵ is optionallysubstituted alkyl. In one embodiment, R⁵ is alkyl. In one embodiment, R⁵is optionally substituted alkoxyl. In one embodiment, R⁵ is alkoxyl. Inone embodiment, R⁵ is optionally substituted aminoalkyl. In oneembodiment, R⁵ is aminoalkyl. In one embodiment, R⁵ is optionallysubstituted alkenyl. In one embodiment, R⁵ is alkenyl. In oneembodiment, R⁵ is optionally substituted alkynyl. In one embodiment, R⁵is alkynyl. In one embodiment, R⁵ is optionally substituted cycloalkyl.In one embodiment, R⁵ is cycloalkyl. In one embodiment, R⁵ is optionallysubstituted cycloalkylalkyl. In one embodiment, R⁵ is cycloalkylalkyl.In one embodiment, R⁵ is optionally substituted aryl. In one embodiment,R⁵ is aryl. In one embodiment, R⁵ is optionally substituted aralkyl. Inone embodiment, R⁵ is aralkyl. In one embodiment, R⁵ is —(CH₂)_(p)—CF₃.In one embodiment, R⁵ is —(CH)_(p)—CN. In one embodiment, R⁵ is—(CH₂)_(p)-nitro. In one embodiment, R⁵ is —(CH₂)_(p)-amino, wherein theamino is optionally substituted. In one embodiment, R⁵ is—(CH₂)_(p)-amino. In one embodiment, R⁵ is —(CH₂)_(p)-hydroxyl, whereinthe hydroxyl is optionally substituted. In one embodiment, R⁵ is—(CH₂)_(p)-hydroxyl. In one embodiment, R⁵ is —(CH₂)_(p)-cycloalkoxyl,wherein the cycloalkoxyl is optionally substituted. In one embodiment,R⁵ is —(CH₂)_(p)-cycloalkoxyl. In one embodiment, R⁵ is C₁-C₄ alkyloptionally substituted with CF₃, CN, nitro, amino, hydroxyl, orcycloalkoxyl, each of which is further optionally substituted. In oneembodiment, R⁵ is C₁-C₄ alkyl optionally substituted with CF₃, CN,nitro, amino, hydroxyl, or cycloalkoxyl. In one embodiment, the alkyl,alkoxyl, aminoalkyl, alkenyl, alkynyl, and cycloalkyl are optionallysubstituted with one or more halo.

In one embodiment, R⁵ and R¹ together with the atoms to which they areattached form an optionally substituted heterocyclyl. In one embodiment,R⁵ and R¹ together with the atoms to which they are attached form aheterocyclyl.

In one embodiment, R⁶ is hydrogen. In one embodiment, R⁶ is halo. In oneembodiment, R⁶ is optionally substituted alkyl. In one embodiment, R⁶ isalkyl. In one embodiment, R⁶ is optionally substituted alkoxyl. In oneembodiment, R⁶ is alkoxyl. In one embodiment, R⁶ is optionallysubstituted aminoalkyl. In one embodiment, R⁶ is aminoalkyl. In oneembodiment, R⁶ is optionally substituted alkenyl. In one embodiment, R⁶is alkenyl. In one embodiment, R⁶ is optionally substituted alkynyl. Inone embodiment, R⁶ is alkynyl. In one embodiment, R⁶ is optionallysubstituted cycloalkyl. In one embodiment, R⁶ is cycloalkyl. In oneembodiment, R⁶ is optionally substituted cycloalkylalkyl. In oneembodiment, R⁶ is cycloalkylalkyl. In one embodiment, R⁶ is optionallysubstituted aryl. In one embodiment, R⁶ is aryl. In one embodiment, R⁶is optionally substituted aralkyl. In one embodiment, R⁶ is aralkyl. Inone embodiment, R⁶ is —(CH₂)_(p)—CF₃. In one embodiment, R⁶ is—(CH₂)_(p)—CN. In one embodiment, R⁶ is —(CH₂)_(p)-nitro. In oneembodiment, R⁶ is —(CH₂)_(p)-amino, wherein the amino is optionallysubstituted. In one embodiment, R⁶ is —(CH₂)_(p)-amino. In oneembodiment, R⁶ is —(CH₂)_(p)-hydroxyl, wherein the hydroxyl isoptionally substituted. In one embodiment, R⁶ is —(CH₂)_(p)-hydroxyl. Inone embodiment, R⁶ is —(CH₂)_(p)-cycloalkoxyl, wherein the cycloalkoxylis optionally substituted. In one embodiment, R⁶ is—(CH₂)_(p)-cycloalkoxyl. In one embodiment, R⁶ is —(CH₂)_(p)-heteroaryl,wherein the heteroaryl is optionally substituted. In one embodiment, R⁶is —(CH₂)_(p)-heteroaryl. In one embodiment, R⁶ is—(CH))_(p)-heterocyclyl, wherein the heterocyclyl is optionallysubstituted. In one embodiment, R⁶ is —(CH₂)_(p)-heterocyclyl. In oneembodiment, the alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, andcycloalkyl are optionally substituted with one or more halo.

In one embodiment, R⁷ is hydrogen. In one embodiment, R⁷ is halo. In oneembodiment, R⁷ is optionally substituted alkyl. In one embodiment, R⁷ isalkyl. In one embodiment, R⁷ is optionally substituted alkoxyl. In oneembodiment, R⁷ is alkoxyl. In one embodiment, R⁷ is optionallysubstituted aminoalkyl. In one embodiment, R⁷ is aminoalkyl. In oneembodiment, R⁷ is optionally substituted alkenyl. In one embodiment, R⁷is alkenyl. In one embodiment, R⁷ is optionally substituted alkynyl. Inone embodiment, R⁷ is alkynyl. In one embodiment, R⁷ is optionallysubstituted cycloalkyl. In one embodiment, R⁷ is cycloalkyl. In oneembodiment, R⁷ is optionally substituted cycloalkylalkyl. In oneembodiment, R⁷ is cycloalkylalkyl. In one embodiment, R⁷ is optionallysubstituted aryl. In one embodiment, R⁷ is aryl. In one embodiment, R⁷is optionally substituted aralkyl. In one embodiment, R⁷ is aralkyl. Inone embodiment, R⁷ is —(CH₂)_(p)—CF₃. In one embodiment, R⁷ is—(CH₂)_(p)—CN. In one embodiment, R⁷ is —(CH₂)_(p)-nitro. In oneembodiment, R⁷ is —(CH₂)_(p)-amino, wherein the amino is optionallysubstituted. In one embodiment, R⁷ is —(CH₂)_(p)-amino. In oneembodiment, R⁷ is —(CH₂)_(p)-hydroxyl, wherein the hydroxyl isoptionally substituted. In one embodiment, R⁷ is —(CH₂)_(p)-hydroxyl. Inone embodiment, R⁷ is —(CH₂)_(p)-cycloalkoxyl, wherein the cycloalkoxylis optionally substituted. In one embodiment, R⁷ is—(CH₂)_(p)-cycloalkoxyl. In one embodiment, R⁷ is —(CH₂)_(p)-heteroaryl,wherein the heteroaryl is optionally substituted. In one embodiment, R⁷is —(CH₂)_(p)-heteroaryl. In one embodiment, R⁷ is—(CH₂)_(p)-heterocyclyl, wherein the heterocyclyl is optionallysubstituted. In one embodiment, R⁷ is —(CH₂)_(p)-heterocyclyl. In oneembodiment, the alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, andcycloalkyl are optionally substituted with one or more halo.

In one embodiment, R⁶ and R⁷ together with the atoms to which they areattached form an optionally substituted aryl. In one embodiment, R⁶ andR⁷ together with the atoms to which they are attached form an aryl. Inone embodiment, R⁶ and R⁷ together with the atoms to which they areattached form an optionally substituted heteroaryl. In one embodiment,R⁶ and R⁷ together with the atoms to which they are attached form aheteroaryl. In one embodiment, R⁶ and R⁷ together with the atoms towhich they are attached form a partially saturated optionallysubstituted cycloalkyl. In one embodiment, R⁶ and R⁷ together with theatoms to which they are attached form a partially saturated cycloalkyl.In one embodiment, R⁶ and R⁷ together with the atoms to which they areattached form an optionally substituted heterocyclyl. In one embodiment,R⁶ and R⁷ together with the atoms to which they are attached form aheterocyclyl.

In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment,m is 2.

In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment,n is 2.

In one embodiment, p is 0. In one embodiment, p is 1. In one embodiment,p is 2.

In one embodiment, at least one of R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ is nothydrogen. In one embodiment, at least one of R¹, R², R³, R⁴, R⁵, and R⁶is not hydrogen (e.g., when R⁷ is absent). In one embodiment, at leastone of R¹, R², R³, R⁴, R⁶, and R⁷ is not hydrogen. In one embodiment, atleast one of R¹, R², R³, R⁴, and R⁶ is not hydrogen (e.g., when R⁷ isabsent). In one embodiment, at least one of R¹ and R² is not hydrogen.In one embodiment, at least one of R³ and R⁴ is not hydrogen. In oneembodiment, at least one of R⁶ and R⁷ is not hydrogen. In oneembodiment, when R⁵ is not hydrogen, at least one of R¹, R², R³, R⁴, R⁶,and R⁷ is not hydrogen. In one embodiment, when R⁵ is not hydrogen, atleast one of R¹, R², R³, R⁴, and R⁶ is not hydrogen (e.g., when R⁷ isabsent). In one embodiment, R⁵ is not hydroxyl. In one embodiment, R⁵ isnot substituted hydroxyl (e.g., alkoxyl). In one embodiment, R⁵ is notalkyl. In one embodiment, R⁵ is not methyl.

In one embodiment, R¹ and R² are not optionally substituted acyl. In oneembodiment, R⁶ and R⁷ are not optionally substituted amide. In oneembodiment, R¹¹ is not optionally substituted amide. In one embodiment,R⁶ and R⁷ are not optionally substituted acyl. In one embodiment, R¹¹ isnot optionally substituted acyl.

In one embodiment, when X and Y are CH₂, R³ and R⁴ are not combinedtogether with R¹ or R² and the atoms to which they are attached to forma ring (e.g., imidazole or imidazoline). In one embodiment, when X and Yare CH₂, R³ and R⁴ are not combined together with R¹ and R² and theatoms to which they are attached to form a ring (e.g., thiazole).

In one embodiment, when X and Y are CH₂, R¹ (or R²) and R⁵ are notcombined together with the atoms to which they are attached form a ring(e.g., pyrrolidine or azetidine).

In one embodiment, when any one of R¹, R², R³, R⁴, R⁵, R⁶, or R⁷ isalkyl or cycloalkyl, the alkyl or cycloalkyl is optionally substitutedwith one or more halo (e.g., fluoro).

Any of the combinations of X, Y, Z¹, Z², Z³, R¹, R², R³, R⁴, R⁵, R⁶, R⁷,m, n, and p are encompassed by this disclosure and specifically providedherein.

In one embodiment, provided herein is a compound of formula (IIa):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶, R⁷, m and n are as defined herein elsewhere.

In one embodiment, m is 0 or 1. In one embodiment, n is 1 or 2. In oneembodiment, m is 0 and n is 1. In one embodiment, n is 0 or 1. In oneembodiment, n is O.

In one embodiment, R⁵ is hydrogen.

In one embodiment, R¹ and R² are each independently hydrogen, C₁-C₄alkyl (e.g., methyl, ethyl, or propyl (e.g., n-propyl or i-propyl)), orC₃-C₆ cycloalkyl (e.g., cyclopropyl). In one embodiment, R¹ and R² areeach independently hydrogen or C₁-C₄ alkyl (e.g., methyl, ethyl, orpropyl (e.g., n-propyl or i-propyl)). In one embodiment, R¹ and R² areeach independently C₁-C₄ alkyl, wherein one or more hydrogen(s) in thealkyl are replaced with deuterium (e.g., CD₃).

In one embodiment, R³ and R⁴ are hydrogen or C₁-C₄ alkyl (e.g., methyl,ethyl, or propyl (e.g., n-propyl or i-propyl)). In one embodiment, R³and R⁴ are hydrogen.

In one embodiment, R⁶ and R⁷ are each independently hydrogen, halo(e.g., F or Cl), C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, or CF₃), aryl(e.g., phenyl), heteroaryl (e.g., pyridyl), heterocyclyl (e.g.,pyrrolidinyl, piperidinyl, or morpholinyl), alkoxyl (e.g., OMe), oraminoalkyl (e.g., NMe₂), each of which is optionally substituted. In oneembodiment, R⁶ and R⁷ are each independently hydrogen, halo, C₁-C₄alkyl, aryl, heteroaryl, heterocyclyl, alkoxyl, or aminoalkyl. In oneembodiment, the C₁-C₄ alkyl is optionally substituted with one or morefluoro. In one embodiment, R⁶ and R⁷ are each independently hydrogen,fluoro, chloro, methyl, CF₃, ethyl, propyl, isopropyl, phenyl, pyridyl,pyrrolidinyl, piperidinyl, morpholinyl, methoxyl, or dimethylamino.

Specific examples include, but are not limited to, the followingcompounds:

In one embodiment, R¹ and R² together with the nitrogen atom to whichthey are attached form a heteroaryl or heterocyclyl, each of which isoptionally substituted. In one embodiment, R¹ and R² together with thenitrogen atom to which they are attached form an optionally substitutedheterocyclyl. In one embodiment, R¹ and R² together with the nitrogenatom to which they are attached form a heteroaryl or heterocyclyl.Examples include, but are not limited to, azetidinyl, pyrrolidinyl,piperidinyl, azepanyl, morpholinyl, imidazolyl, piperazinyl, andN-methyl-piperazinyl. Specific examples include, but are not limited to,the following compounds:

In one embodiment, R¹ and R³ together with the atoms to which they areattached form an optionally substituted heterocyclyl ring (e.g.,pyrrolidine, including, e.g., unsubstituted pyrrolidine andN-methyl-pyrrolidine). Specific examples include, but are not limitedto, the following compounds:

In one embodiment, R³ and R⁴ together with the atom to which they areattached form a cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl) or heterocyclyl (e.g., tetrahydrofuranyl) ring, each ofwhich is optionally substituted. Specific examples include, but are notlimited to, the following compounds:

In one embodiment, R⁶ and R⁷ together with the atoms to which they areattached form an aryl (e.g., phenyl) or cycloalkyl (e.g., 5-, 6-, or7-membered) ring, each of which is optionally substituted (e.g., by oneor more halo or phenyl). In one embodiment, R⁶ and R⁷ together with theatoms to which they are attached form an optionally substituted aryl. Inone embodiment, R⁶ and R⁷ together with the atoms to which they areattached form an aryl. Examples include, but are not limited to, phenyl,cyclopentenyl, cyclohexenyl, and cycloheptenyl. Specific examplesinclude, but are not limited to, the following compounds:

In one embodiment, R¹ and R⁵ together with the atoms to which they areattached form an optionally substituted heterocyclyl. In one embodiment,R¹ and R⁵ together with the atoms to which they are attached form aheterocyclyl. Examples include, but are not limited to, pyrrolidinyl andpiperidinyl. Specific examples include, but are not limited to, thefollowing compounds:

In one embodiment, R¹ and R⁵ together with the atoms to which they areattached form an optionally substituted heterocyclyl (e.g., piperidinyl)and R⁶ and R⁷ together with the atoms to which they are attached form anoptionally substituted aryl (e.g., phenyl). In one embodiment, R¹ and R⁵together with the atoms to which they are attached form a heterocyclyland R⁶ and R⁷ together with the atoms to which they are attached form anaryl. Specific examples include, but are not limited to, the followingcompound:

In one embodiment, m is 0 and R³ and R⁴ are combined together to form adouble bond and together with R¹ and/or R² and the atoms to which theyare attached form an optionally substituted heteroaryl. In oneembodiment, the heteroaryl contains one or more heteroatoms selectedfrom N, O, and S. Examples include, but are not limited to, imidazolyl,pyrazolyl, or thiazolyl. Specific examples include, but are not limitedto, the following compounds:

In one embodiment, m is 1. Specific examples include, but are notlimited to, the following compound:

In one embodiment, n is 2. In one embodiment, R¹, R², R⁶, and R⁷ areeach independently hydrogen or optionally substituted C₁-C₄ alkyl (e.g.,methyl or ethyl). Specific examples include, but are not limited to thefollowing compounds:

In one embodiment, R⁵ is alkyl. In one embodiment, R⁵ is C₁-C₄ alkyl. Inone embodiment, R⁵ is methyl. Specific examples include, but are notlimited to, the following compound:

In one embodiment, provided herein is a compound of formula (IIb):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶, R⁷, m and n are as defined herein elsewhere.

In one embodiment, provided herein is a compound of formula (IIc):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶, R⁷, m and n are as defined herein elsewhere.

In one embodiment, R⁵ is OH. Specific examples include, but are notlimited to, the following compound:

In one embodiment, R⁵ is hydrogen.

In one embodiment, n is 0. In one embodiment, R¹ and R² are eachindependently hydrogen or optionally substituted C₁-C₄ alkyl (e.g.,methyl or ethyl). In one embodiment, R⁶ and R⁷ are each independentlyhydrogen, halo (e.g., F or Cl), or optionally substituted C₁-C₄ alkyl(e.g., methyl or ethyl). Specific examples include, but are not limitedto, the following compounds:

In one embodiment, n is 1. In one embodiment, R¹ and R² are eachindependently hydrogen or optionally substituted C₁-C₄ alkyl (e.g.,methyl or ethyl). In one embodiment, R¹ and R² together with the atom towhich they are attached form an optionally substituted heterocyclyl(e.g., piperidinyl). In one embodiment, R⁶ and R⁷ are each independentlyhydrogen or optionally substituted C₁-C₄ alkyl (e.g., methyl or ethyl).Specific examples include, but are not limited to, the followingcompounds:

In one embodiment, provided herein is a compound of formula (IIIa):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶, R⁷, m and n are as defined herein elsewhere.

In one embodiment, R¹, R², R⁶, and R⁷ are each independently hydrogen oroptionally substituted C₁-C₄ alkyl (e.g., methyl or ethyl). Specificexamples include, but are not limited to, the following compounds:

In one embodiment, provided herein is a compound of formula (IIIb):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶, R⁷, m and n are as defined herein elsewhere.

In one embodiment, provided herein is a compound of formula (IIIc):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶, R⁷, m and n are as defined herein elsewhere.

In one embodiment, provided herein is a compound of formula (IVa):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶, R⁷, m and n are as defined herein elsewhere.

In one embodiment, m is 0 or 1. In one embodiment, n is 1 or 2. In oneembodiment, m is 0 and n is 1. In one embodiment, n is 0 or 1. In oneembodiment, n is O.

In one embodiment, R⁵ is hydrogen.

In one embodiment, R¹ and R² are each independently hydrogen, C₁-C₄alkyl (e.g., methyl, ethyl, or propyl (e.g., n-propyl or i-propyl)), orC₃-C₆ cycloalkyl (e.g., cyclopropyl). In one embodiment, R¹ and R² areeach independently hydrogen or C₁-C₄ alkyl (e.g., methyl, ethyl, orpropyl (e.g., n-propyl or i-propyl)). In one embodiment, R¹ and R² areeach independently C₁-C₄ alkyl, wherein one or more hydrogen(s) in thealkyl are replaced with deuterium (e.g., CD₃).

In one embodiment, R³ and R⁴ are hydrogen or C₁-C₄ alkyl (e.g., methyl,ethyl, or propyl (e.g., n-propyl or i-propyl)). In one embodiment, R³and R⁴ are hydrogen.

In one embodiment, R⁶ and R⁷ are each independently hydrogen, halo(e.g., F or Cl), C₁-C₄ alkyl (e.g., methyl, ethyl, propyl, or CF₃), aryl(e.g., phenyl), heteroaryl (e.g., pyridyl), heterocyclyl (e.g.,pyrrolidinyl, piperidinyl, or morpholinyl), alkoxyl (e.g., OMe), oraminoalkyl (e.g., NMe₂), each of which is optionally substituted. In oneembodiment, R⁶ and R⁷ are each independently hydrogen, halo, C₁-C₄alkyl, aryl, heteroaryl, heterocyclyl, alkoxyl, or aminoalkyl. In oneembodiment, the C₁-C₄ alkyl is optionally substituted with one or morefluoro. In one embodiment, R⁶ and R⁷ are each independently hydrogen,fluoro, chloro, methyl, CF₃, ethyl, propyl, isopropyl, phenyl, pyridyl,pyrrolidinyl, piperidinyl, morpholinyl, methoxyl, or dimethylamino.

Specific examples include, but are not limited to, the followingcompounds:

In one embodiment, m is 1. Specific examples include, but are notlimited to, the following compounds:

In one embodiment, R¹ and R² together with the nitrogen atom to whichthey are attached form a heteroaryl or heterocyclyl, each of which isoptionally substituted. In one embodiment, R¹ and R² together with thenitrogen atom to which they are attached form an optionally substitutedheterocyclyl (e.g., pyrrolidinyl or piperidinyl). Examples include, butare not limited to, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl,morpholinyl, imidazolyl, piperazinyl, and N-methyl-piperazinyl. Specificexamples include, but are not limited to, the following compounds:

In one embodiment, R¹ and R³ together with the atoms to which they areattached form an optionally substituted heterocyclyl ring (e.g.,pyrrolidine, including, e.g., unsubstituted pyrrolidine andN-methyl-pyrrolidine). Specific examples include, but are not limitedto, the following compounds:

In one embodiment, R¹ and R⁵ together with the atoms to which they areattached form an optionally substituted heterocyclyl. Examples include,but are not limited to, pyrrolidinyl and piperidinyl. Specific examplesinclude, but are not limited to, the following compounds:

In one embodiment, R⁶ and R⁷ together with the atoms to which they areattached form an aryl (e.g., phenyl) or cycloalkyl (e.g., 5-, 6-, or7-membered) ring, each of which is optionally substituted (e.g., by oneor more halo or phenyl). In one embodiment, R⁶ and R⁷ together with theatoms to which they are attached form an optionally substituted aryl.Examples include, but are not limited to, phenyl, cyclopentenyl,cyclohexenyl, and cycloheptenyl. Specific examples include, but are notlimited to, the following compounds:

In one embodiment, R¹ and R⁵ together with the atoms to which they areattached form an optionally substituted heterocyclyl (e.g.,pyrrolidinyl) and R⁶ and R⁷ together with the atoms to which they areattached form an optionally substituted aryl (e.g., phenyl). Specificexamples include, but are not limited to, the following compound:

In one embodiment, m is 0 and R³ and R⁴ are combined together to form adouble bond and together with R¹ and/or R² and the atoms to which theyare attached form an optionally substituted heteroaryl. In oneembodiment, the heteroaryl contains one or more heteroatoms selectedfrom N, O, and S. Examples include, but are not limited to, imidazolyl,pyrazolyl, or thiazolyl. Specific examples include, but are not limitedto, the following compounds:

In one embodiment, provided herein is a compound of formula (IVb):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶, R⁷, m and n are as defined herein elsewhere.

In one embodiment, provided herein is a compound of formula (IVc):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶, R⁷, m and n are as defined herein elsewhere.

In one embodiment, n is 0. In one embodiment, R¹ and R² are eachindependently hydrogen or optionally substituted C₁-C₄ alkyl (e.g.,methyl or ethyl). In one embodiment, R⁶ and R⁷ are each independentlyhydrogen, halo (e.g., F or Cl), or optionally substituted C₁-C₄ alkyl(e.g., methyl or ethyl). Specific examples include, but are not limitedto, the following compounds:

In one embodiment, n is 1. In one embodiment, R¹ and R² are eachindependently hydrogen or optionally substituted C₁-C₄ alkyl (e.g.,methyl or ethyl). In one embodiment, R¹ and R² together with the atom towhich they are attached form an optionally substituted heterocyclyl(e.g., piperidinyl). In one embodiment, R⁶ and R⁷ are each independentlyhydrogen or optionally substituted C₁-C₄ alkyl (e.g., methyl or ethyl).Specific examples include, but are not limited to, the followingcompounds:

In one embodiment, R⁶ and R⁷ together with the atoms to which they areattached form an aryl (e.g., phenyl) or cycloalkyl (e.g., 5-, 6-, or7-membered) ring, each of which is optionally substituted (e.g., by oneor more halo or phenyl). In one embodiment, R⁶ and R⁷ together with theatoms to which they are attached form an optionally substituted aryl.Examples include, but are not limited to, phenyl, cyclopentenyl,cyclohexenyl, and cycloheptenyl. Specific examples include, but are notlimited to, the following compounds:

In one embodiment, provided herein is a compound of formula (V):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶, Z¹, Z³, X, Y, m and n are as defined hereinelsewhere. In one embodiment, Z¹ is N and Z³ is S. In one embodiment, Z¹is S and Z³ is N. In one embodiment, X and Y is CH₂. In one embodiment,m is 0 and n is 1. In one embodiment, R¹ and R² are each independentlyhydrogen or optionally substituted C₁-C₄ alkyl (e.g., methyl or ethyl).In one embodiment, R³, R⁴, and R⁵ are hydrogen. In one embodiment, R⁶ ishydrogen, halo (e.g., F or Cl), optionally substituted C₁-C₄ alkyl(e.g., methyl or ethyl), or optionally substituted amino (e.g.,aminoalkyl, such as methylamino). Specific examples include, but are notlimited to, the following compounds:

In one embodiment, provided herein is a compound of formula (VI):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

two of Z¹, Z², and Z³ are C, and one of Z¹, Z², and Z³ is S;

R¹ and R² are each independently (i) hydrogen, alkyl, alkoxyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, oraralkyl, each of which is optionally substituted; or (ii) —(CH₂)_(p)—R⁸,wherein R⁸ is SO₂alkyl or SO₂aryl, each of which is optionallysubstituted; or (iii) R¹ and R² together with the nitrogen atom to whichthey are attached form an optionally substituted heterocyclyl orheteroaryl;

R³ and R⁴ are each independently (i) hydrogen, alkyl, alkoxyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, oraralkyl, each of which is optionally substituted; or (ii) —(CH₂)_(p)—R⁹,wherein R⁹ is CF₃, CN, nitro, amino, hydroxyl, or cycloalkoxyl, each ofwhich is optionally substituted; or (iii) R³ and R⁴ together with thecarbon atom to which they are attached form an optionally substitutedcycloalkyl or heterocyclyl; or (iv) R³ and R¹ together with the atoms towhich they are attached form an optionally substituted heterocyclyl, andR⁴ is (i) or (ii); or (v) R³ and R⁴ are combined together to form adouble bond and together with R¹ and/or R² and the atoms to which theyare attached form an optionally substituted heteroaryl;

R⁵ is (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which isoptionally substituted; or (ii) —(CH₂)_(p)—R¹⁰, wherein R¹⁰ is CF₃, CN,nitro, amino, hydroxyl, or cycloalkoxyl, each of which is optionallysubstituted; or (iii) R⁵ and R¹ together with the atoms to which theyare attached form an optionally substituted heterocyclyl;

R⁶ and R⁷ are each independently (i) hydrogen, halo, alkyl, alkoxyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, oraralkyl, each of which is optionally substituted; or (ii)—(CH₂)_(p)—R¹¹, wherein R¹¹ is CF₃, CN, nitro, amino, hydroxyl,cycloalkoxyl, heteroaryl, or heterocyclyl, each of which is optionallysubstituted; or (iii) R⁶ and R⁷ together with the atoms to which theyare attached form an optionally substituted aryl, heteroaryl, cycloalkylor heterocyclyl ring; and

m is 0, 1, or 2;

each occurrence of p is independently 0, 1, or 2.

In one embodiment, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, Z¹, Z², Z³, and m are asdefined herein elsewhere. In one embodiment, Z¹ and Z² are C, and Z³ isS. In one embodiment, Z¹ is S, and Z² and Z³ are C. In one embodiment, mis 0. In one embodiment, R¹ and R² are each independently hydrogen oroptionally substituted C₁-C₄ alkyl (e.g., methyl or ethyl). In oneembodiment, R³ and R⁴ are hydrogen. In one embodiment, R⁵ is hydrogen.In one embodiment, R¹ and R⁵ together with the atoms to which they areattached form an optionally substituted heterocyclyl (e.g.,pyrrolidinyl). In one embodiment, R⁶ and R⁷ are each independentlyhydrogen, halo (e.g., F or CO, or optionally substituted C₁-C₄ alkyl(e.g., methyl or ethyl). Specific examples include, but are not limitedto, the following compounds:

It should be noted that if there is a discrepancy between a depictedstructure and a chemical name given that structure, the depictedstructure is to be accorded more weight. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it or mixtures thereof. Where the compound providedherein contains an alkenyl or alkenylene group, the compound may existas one of or a mixture of geometric cis/trans (or Z/E) isomers. Wherestructural isomers are inter-convertible, the compound may exist as asingle tautomer or a mixture of tautomers. This can take the form ofproton tautomerism in the compound that contains, for example, an imino,keto, or oxime group; or so-called valence tautomerism in the compoundthat contains, for example, an aromatic moiety. It follows that a singlecompound may exhibit more than one type of isomerism.

The compounds provided herein may be enantiomerically pure ordiastereomerically pure, such as a single enantiomer or a singlediastereomer, or be stereoisomeric mixtures, such as a mixture ofenantiomers and/or diastereomers, e.g., a racemic or enantioenrichedmixture of two enantiomers; or a mixture of two or more diastereomers.In some instances, for compounds that undergo epimerization in vivo, oneof skill in the art will recognize that administration of a compound inits (R) form is equivalent to administration of the compound in its (S)form, and vice versa. Conventional techniques for thepreparation/isolation of individual enantiomers or diastereomers includesynthesis from a suitable optically pure precursor, asymmetric synthesisfrom achiral starting materials, or resolution of a stereomeric mixture,for example, by chiral chromatography, recrystallization, resolution,diastereomeric salt formation, or derivatization into diastereomericadducts followed by separation.

When the compound provided herein contains an acidic or basic moiety, itmay also be provided as a pharmaceutically acceptable salt (See, Bergeet al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of PharmaceuticalSalts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA,Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,aspartic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, boric acid, camphoric acid, (+)-camphoric acid,camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid,caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid,cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, D-gluconic acid, glucuronic acid, D-glucuronic acid,glutamic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,isoethonic acid; (+)-L-lactic acid, (±)-DL-lactic acid, lactobionicacid, lauric acid, maleic acid, malic acid, (−)-L-malic acid, malonicacid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonicacid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid,nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid,palmitic acid, pamoic acid, perchloric acid, phosphoric acid,pyroglutamic acid, pyroglutamic acid, L-pyroglutamic acid, saccharicacid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearicacid, succinic acid, sulfuric acid, tannic acid, tartaric acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid,undecylenic acid, and valeric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, potassium carbonate,zinc hydroxide, sodium hydroxide, or ammonia; and organic bases, such asprimary, secondary, tertiary, and quaternary, aliphatic and aromaticamines, including L-arginine, benethamine, benzathine, choline, deanol,diethanolamine, diethylamine, dimethylamine, dipropylamine,diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine,ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine,1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine,methylamine, piperidine, piperazine, propylamine, pyrrolidine,1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline,isoquinoline, secondary amines, triethanolamine, trimethylamine,triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

Unless otherwise specified, the term “compound” referred to herein, suchas, e.g., a compound of formula (I), (IIa), (IIb), (IIc), (Ma), (IIIb),(Mc), (IVa), (IVb), (IVc), (V), or (VI) is intended to encompass one ormore of the following: a free base of the compound or a salt thereof, astereoisomer or a mixture of two or more stereoisomers, a solid form(e.g., a crystal form or an amorphous form) or a mixture of two or moresolid forms thereof, or a solvate (e.g., a hydrate) thereof. In certainembodiments, the term “compound” referred to herein is intended toencompass a pharmaceutical acceptable form of the compound, includingbut not limited to, a free base, a pharmaceutically acceptable salt, astereoisomer or a mixture of two or more stereoisomers, a solid form(e.g., a crystal form or an amorphous form) or a mixture of two or moresolid forms, a solvate (e.g., a hydrate), or a cocrystal thereof. In oneembodiment, the term “compound” referred to herein, such as, e.g., acompound of formula (I), (IIa), (IIb), (IIc), (IIIc), (IIb), (IIc),(IVa), (IVb), (IVc), (V), or (VI) is intended to encompass a solvate(e.g., a hydrate) thereof.

The compound provided herein may also be provided as a prodrug, which isa functional derivative of the compound, for example, of Formula (I) andis readily convertible into the parent compound in vivo. Prodrugs areoften useful because, in some situations, they may be easier toadminister than the parent compound. They may, for instance, bebioavailable by oral administration whereas the parent compound is not.The prodrug may also have enhanced solubility in pharmaceuticalcompositions over the parent compound. A prodrug may be converted intothe parent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4,221-294; Morozowich et al. in “Design of Biopharmaceutical Propertiesthrough Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977;“Bioreversible Carriers in Drug in Drug Design, Theory and Application,”Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard,Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287;Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen etal., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med.Chem. 1996, 671-696; Asgharnejad in “Transport Processes inPharmaceutical Systems,” Amidon et al., Ed., Marcell Dekker, 185-218,2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15,143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209;Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm.Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17,179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher etal., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., MethodsEnzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72,324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877;Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al.,Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood,Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev.1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al.,Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug DeliveryRev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39,63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

C. Synthetic Schemes

Schemes below provide exemplary synthetic methods for the preparation ofthe compounds provided herein. One of ordinary skills in the art willunderstand that similar methods may be employed to prepare the compoundsprovided herein. In other words, one of ordinary skills in the art willrecognize that suitable adjustments to reagents, protecting groups,reaction conditions, and reaction sequences may be employed to prepare adesired embodiment. The reactions may be scaled upwards or downwards tosuit the amount of material to be prepared.

In one embodiment, the compound of formula (I) may be prepared followingSchemes 1-3, using suitable starting materials known in the art and/oravailable from a commercial source. In one embodiment, the hydroxyalkylthiophene starting material of Schemes 1-3 is known or may be preparedusing known methods starting from commercially available compounds. Inone embodiment, the amino-aldehyde dimethyl acetal starting material ofSchemes 1-3 is known or may be prepared using known methods startingfrom commercially available compounds. It is understood that otheracetals, such as, e.g., diethyl acetals, may also be used as thestarting material of the reaction of Schemes 1-3. In one embodiment, thereaction is carried out in an ether solvent, such as, e.g., 1,4-dioxane.In one embodiment, other acids than trifluoromethyl sulfonic acid may beused to facilitate the reaction. In some embodiments, R¹, R², R³, R⁴,R⁵, R⁶, or R⁷ may be further transformed to suitable functional groups,as described for formula (I), after the ring formation step of Schemes1-3, using methods known in the art. Specific and non-limiting examplesof such transformations are described in the General Procedures in theExamples.

In one embodiment, the compound of formula (I) may be prepared followingSchemes 4-6, using suitable nucleophilic starting materials known in theart and/or available from a commercial source. In one embodiment, R₁₂may be cyano, or a suitable alkyl, alkenyl, alkynyl, heteroalkyl, aryl,heteroaryl, cycloalkyl, or heterocyclyl, among others. In oneembodiment, the thiophene ketone starting material of Schemes 4-6 isknown or may be prepared using known methods starting from commerciallyavailable compounds. The hydroxyl compound of Schemes 4-6 may betransformed to a compound of formula (I) using methods known in the art.In some embodiments, R¹, R², R³, R⁴, R⁵, R⁶, or R⁷ may be furthertransformed to suitable functional groups, as described for formula (I)using methods known in the art. Specific and non-limiting examples ofsuch transformations are described in the General Procedures in theExamples.

In one embodiment, the compound of formula (I) may be prepared followingSchemes 7-9, using suitable starting materials known in the art and/oravailable from a commercial source. In one embodiment, R₁₃ is a suitableleaving group, such as, e.g., halo, such as chloro, or R₁₃ may be agroup, such as hydroxyl, that can be transformed to a suitable leavinggroup, such as, e.g., tosylate, inflate, mesylate, or nosylate, or R₁₃itself may be such hydroxyl-derived leaving group. In one embodiment,the hydroxyalkyl thiophene starting material of Schemes 7-9 is known ormay be prepared using known methods starting from commercially availablecompounds. In one embodiment, the dimethyl acetal starting material ofSchemes 7-9 is known or may be prepared using known methods startingfrom commercially available compounds. It is understood that otheracetals, such as, e.g., diethyl acetals, may also be used as thestarting material of the reaction of Schemes 7-9. In one embodiment, thereaction is carried out in an ether solvent, such as, e.g., 1,4-dioxane.In one embodiment, other acids than trifluoromethyl sulfonic acid may beused to facilitate the reaction. In some embodiments, R², R³, R⁴, R⁵,R⁶, or R⁷ may be further transformed to suitable functional groups, asdescribed for formula (I) using methods known in the art. Specific andnon-limiting examples of such transformations are described in theGeneral Procedures in the Examples.

In certain embodiments, the compound of formula (I) is prepared as amixture of two or more stereoisomers or diastereoisomers. In oneembodiment, the stereoisomers or diastereoisomers are separated usingtechniques known to those skilled in the art, including but not limitedto, chiral column chromatography and chiral resolution by forming a saltwith a suitable chiral counterion. In certain embodiments, the compoundof formula (I) is prepared following one or more stereoselectivereaction(s). In some embodiment, the compound of formula (I) is preparedas a substantially pure stereoisomer.

D. Methods of Treatment, Prevention, and/or Management

1. In Vivo Assays

In one embodiment, provided herein is a method of administering acompound provided herein, or a pharmaceutically acceptable salt orstereoisomer thereof, in a disease model that is known in the art. Inone embodiment, the disease model is an animal model. In one embodiment,provided herein is a method of administering a compound provided herein,or a pharmaceutically acceptable salt or stereoisomer thereof, in ananimal model that is predictive of efficacy in the treatment of certaindiseases in human. The method comprises administering a compoundprovided herein, or a pharmaceutically acceptable salt or stereoisomerthereof, in a subject. In one embodiment, the method comprisesadministering a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable salt or stereoisomer thereof,in a subject. In one embodiment, the method comprises treatment of atest subject (e.g., a mouse or rat) with a compound provided herein, ora pharmaceutically acceptable salt or stereoisomer thereof. In oneembodiment, the method comprises treatment of a test subject (e.g., amouse or rat) with a compound provided herein, or a pharmaceuticallyacceptable salt or stereoisomer thereof, as well as a referencecompound, either in separate animal groups (e.g., administer a referencecompound in a control group and administer a compound provided herein ina test group) or in the same animal group (e.g., as combinationtherapy). In one embodiment, the in vivo activity of the compoundprovided herein is dose dependent.

In one embodiment, the compounds provided herein are active in animalmodels of psychosis such as Pre-Pulse Inhibition (PPI) and PCP-inducedhyperlocomotion. These two models have been used in the development ofseveral antipsychotics, including olanzapine (ZYPREXA) (Bakshi andGeyer, Psychopharmacology 1995, 122, 198-201) and quetapine (SEROQUEL)(Swedlow et al., J. Pharm. Exp. Ther., 1996, 279, 1290-99), and arepredictive of efficacy in human psychotic patients. In one embodiment,compounds that are active in in vivo models of psychosis are furtheroptimized to improve the potency in the in vivo assays and drug-likeproperties such as, e.g., solubility and lipophilicity. Given the exactmolecular basis of certain diseases such as schizophrenia are poorlyunderstood, this approach allows the use of predictive andwell-validated animal models to develop compounds with establishedefficacy without focusing on specific molecular targets that may or maynot translate to human efficacy in the clinic.

2. Treatment, Prevention, and/or Management

In one embodiment, provided herein is a method of treating, preventing,and/or managing various disorders, including, but not limited to,neurological disorders. In one embodiment, provided herein is a methodof treating, preventing, and/or managing one or more symptoms of aneurological disorder. In one embodiment, the method comprisesadministering to a subject (e.g., human) a therapeutically orprophylactically effective amount of a composition or a compoundprovided herein or a pharmaceutically acceptable salt or stereoisomerthereof. In one embodiment, the subject is a human. In one embodiment,the subject is an animal. In one embodiment, the compounds providedherein are highly brain penetrable in the subject. In certainembodiments, the efficacious concentration of a compound provided hereinis less than 10 nM, less than 100 nM, less than 1 μM, less than 10 μM,less than 100 μM, or less than 1 mM. In one embodiment, a compound'sactivity may be assessed in various art-recognized animal models asdescribed herein elsewhere or known in the literature.

In one embodiment, without being limited by a particular theory, thetreatment, prevention, and/or management is done by administering acompound provided herein that has shown in vivo efficacy in an animalmodel predictive of antipsychotic activity in humans. The phenotypicapproach to develop antipsychotics has been used in psychopharmacology,with the antipsychotic chlorpromazine developed in this way. Thephenotypic approach may also offer advantages over compounds developedby traditional in vitro based drug discovery approach, because thecompounds developed using the phenotypic approach have establishedpharmaceutical properties and in vivo activity, rather than activitytoward a given molecular target, which may be less predictive and leadto attrition at later stages of, for example, clinical development.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a neurological disorder, including schizophrenia,schizophrenia spectrum disorder, acute schizophrenia, chronicschizophrenia, NOS schizophrenia, schizoid personality disorder,schizotypal personality disorder, delusional disorder, psychosis,psychotic disorder, brief psychotic disorder, shared psychotic disorder,psychotic disorder due to a general medical condition, drug-inducedpsychosis (e.g., cocaine, alcohol, amphetamine), psychoaffectivedisorder, aggression, delirium, Parkinson's psychosis, excitativepsychosis, Tourette's syndrome, organic or NOS psychosis, seizure,agitation, post-traumatic stress disorder, behavior disorder,neurodegenerative disease, Alzheimer's disease, Parkinson's disease,dyskinesias, Huntington's disease, dementia, mood disorder, anxiety,affective disorders (e.g., depression, e.g., major depressive disorderand dysthymia; bipolar disorder, e.g., biopolar depressive disorder;manic disorder; seasonal affective disorder; and attention deficitdisorder (ADD) and attention deficit hyperactivity disorder (ADHD)),obsessive-compulsive disorder, vertigo, epilepsy, pain (e.g.,neuropathic pain, sensitization accompanying neuropathic pain, andinflammatory pain), fibromyalgia, migraine, cognitive impairment,movement disorder, restless leg syndrome (RLS), multiple sclerosis,sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness,jet lag, drowsy side effect of medications, insomnia, substance abuse ordependency (e.g., nicotine, cocaine), addiction, eating disorder, sexualdysfunction, hypertension, emesis, Lesche-Nyhane disease, Wilson'sdisease, autism, Huntington's chorea, and premenstrual dysphoria,comprising administering to a subject an effective amount of a compoundprovided herein, or a pharmaceutically acceptable salt or stereoisomerthereof.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a disorder related to psychosis, schizophrenia, ADHD,mood disorder or affective disorder such as depression and anxiety,comprising administering to a subject an effective amount of a compoundprovided herein. For example, without being limited by a particulartheory, the compounds provided herein may improve the gating deficits ofDBA/2 mice seen in the pre-pulse inhibition (PPI) test and reverse themethamphe-tamine-induced hyperlocomotor activity. Without being limitedto a particular theory, the compounds provided herein may: 1) reversethe amphetamine-induced hyper-locomotor activity; 2) be useful asantipsychotic agents and dosed sparing; 3) improve attention andmodulate impulsivity; 4) improve learning parameters in ADHD; 5) enhancelearning ability and reduce anxiety in behavioral tests; and/or 6) havean anti-depressant effect.

In another embodiment, provided herein is a method of treating,preventing, and/or managing a disorder related to cognitive impairments,such as Alzheimer's disease, Parkinson's disease, schizophrenia, andattention deficit hyperactivity disorder (ADHD), and the like,comprising administering to a subject an effective amount of a compoundprovided herein. For example, without being limited by a particulartheory, the compounds provided herein may have pro-cognitive effects,such as passive avoidance, novel object recognition, social recognition,and attention-set shifting. Further, without being limited by aparticular theory, the compounds provided herein may improve socialmemory, increase the acquisition of an environment, and reversescopolamine-induced deficits. The compounds provided herein may alsoreverse scopolamine-induced deficits in a passive avoidance memory test.

In another embodiment, provided herein is a method of treating,preventing, and/or managing a disorder associated with excessive daytimesleepiness, such as, narcolepsy, Parkinson's disease, multiplesclerosis, shift workers, jet lag, relief of side effects of othermedications, and the like, comprising administering to a subject aneffective amount of a compound provided herein. For example, withoutbeing limited by a particular theory, the compounds provided herein mayhave wake promoting effects.

In another embodiment, provided herein is a method of treating,preventing, and/or managing a sleeping disorder, such as insomnia,comprising administering to a subject an effective amount of a compoundprovided herein. For example, without being limited by a particulartheory, the compounds provided herein may improve wakefulness and leadto an improved sleep pattern, and therefore the compounds providedherein may be useful in treating insomnia.

In another embodiment, provided herein is a method of treating,preventing, and/or managing substance abuse, comprising administering toa subject an effective amount of a compound provided herein. Forexample, without being limited by a particular theory, the compoundsprovided herein may alter methamphetamine self-administration in rats,and therefore the compounds provided herein may ameliorate the cravingfor addictive drugs.

In another embodiment, provided herein is a method of using thecompounds provided herein as psycho-stimulants, which may lack the abuseliabilities generally associated with other classes ofpsycho-stimulants. Without being limited by a particular theory, thecompounds provided herein may increase the levels of histamine,dopamine, norepinephrine, and/or acetylcholine in the prefrontalcortical area, which is consistent with their pro-cognitive effects andtheir wake promoting effects seen in animal models. For example, thecompounds provided herein may increase dopamine in the frontal cortexbut not the striatum. The compounds provided herein may not induceincreased locomotor activity or sensitization that is associated withother psycho-stimulus.

In another embodiment, provided herein is a method of treating,preventing, and/or managing a disorder such as seizure, epilepsy,vertigo, and pain, comprising administering to a subject an effectiveamount of a compound provided herein. For example, without being limitedby a particular theory, the compounds provided herein may be protectiveagainst pentylene-tetrazole (PTZ) and electrical-induced seizures. Thecompounds provided herein may increase the seizure threshold in humans.The compounds provided herein may decrease electrical discharge fromafferent neurons in an inner ear preparation. Further, without beinglimited by a particular theory, the compounds provided herein mayincrease the threshold for neuropathic pain, which is shown in modelssuch as the chronic constriction injure (CCI) model, herpesvirus-induced model, and capsaicin-induced allodynia model. Therefore,in some embodiments, the compounds provided herein are employed fortheir analgesic effects to treat, prevent, and/or manage disordersinvolving pain and the sensitization that accompanies many neuropathicpain disorders.

In another embodiment, provided herein is a method of treating,preventing, and/or managing a movement disorder, such as Parkinson'sdisease, restless leg syndrome (RLS), and Huntington's disease,comprising administering to a subject an effective amount of a compoundprovided herein.

In some embodiments, a compound provided herein is active in at leastone model, which can be used to measure the activity of the compound andestimate the efficacy in treating a neurological disorder. For example,when the model is for psychosis (e.g., PCP Hyperactivity Model orPrepulse Inhibition of Startle Model), a compound is active when thecompound reduces PCP induced hyperactivity in mice by a statisticallysignicant amount compared to a vehicle, or when the compound reversesthe disruption of prepulse inhibition (PPI) induced by PCP in mice.

In other embodiments, provided herein is a method of effecting atherapeutic effect as described herein elsewhere. The method comprisesadministering to a subject (e.g., a mammal) a therapeutically effectiveamount of a compound or composition provided herein. The particulartherapeutic effects may be measured using any model system known in theart and described herein, such as those involving an animal model of adisease.

In some embodiments, the neurological disorder is: depression (e.g.,major depressive disorder or dysthymia); bipolar disorder, seasonalaffective disorder; cognitive deficit; fibromyalgia; pain (e.g.,neuropathic pain); sleep related disorder (e.g., sleep apnea, insomnia,narcolepsy, cataplexy) including those sleep disorders which areproduced by psychiatric conditions; chronic fatigue syndrome; attentiondeficit disorder (ADD); attention deficit hyperactivity disorder (ADHD);restless leg syndrome; schizophrenia; anxieties (e.g., general anxietydisorder, social anxiety disorder, panic disorder); obsessive compulsivedisorder; post-traumatic stress disorder; seasonal affective disorder(SAD); premenstrual dysphoria; post-menopausal vasomotor symptoms (e.g.,hot flashes, night sweats); neurodegenerative disease (e.g., Parkinson'sdisease, Alzheimer's disease and amyotrophic lateral sclerosis); manicdisorder; dysthymic disorder; cyclothymic disorder; obesity; andsubstance abuse or dependency (e.g., cocaine addiction, nicotineaddiction). In another embodiment, the compounds provided herein areuseful to treat, prevent, and/or manage two or moreconditions/disorders, which are co-morbid, such as psychosis anddepression.

Neurological disorders may also include cerebral function disorders,including without limitation, senile dementia, Alzheimer's typedementia, cognition, memory loss, amnesia/amnestic syndrome, epilepsy,disturbances of consciousness, coma, lowering of attention, speechdisorder, Lennox syndrome, autism, and hyperkinetic syndrome.

Neuropathic pain includes, without limitation, post herpetic (orpost-shingles) neuralgia, reflex sympathetic dystrophy/causalgia ornerve trauma, phantom limb pain, carpal tunnel syndrome, and peripheralneuropathy (such as diabetic neuropathy or neuropathy arising fromchronic alcohol use).

Other exemplary diseases and conditions that may be treated, prevented,and/or managed using the methods, compounds, and/or compositionsprovided herein include, but are not limited to: obesity; migraine ormigraine headache; and sexual dysfunction, in men or women, includingwithout limitation sexual dysfunction caused by psychological and/orphysiological factors, erectile dysfunction, premature ejaculation,vaginal dryness, lack of sexual excitement, inability to obtain orgasm,and psycho-sexual dysfunction, including without limitation, inhibitedsexual desire, inhibited sexual excitement, inhibited female orgasm,inhibited male orgasm, functional dyspareunia, functional vaginismus,and atypical psychosexual dysfunction.

In one embodiment, the neurological disorder is excessive daytimesleepiness. In another embodiment, the neurological disorder is acognitive impairment. In another embodiment, the neurological disorderis a mood disorder. In another embodiment, the neurological disorder isan affective disorder. In another embodiment, the neurological disorderis a movement disorder. In another embodiment, the neurological disorderis schizophrenia. In another embodiment, the neurological disorder is anattention disorder. In another embodiment, the neurological disorder isan anxiety disorder. In another embodiment, the neurological disorder isseizure. In another embodiment, the neurological disorder is psychosis.In another embodiment, the neurological disorder is epilepsy. In anotherembodiment, the neurological disorder is vertigo. In another embodiment,the neurological disorder is pain. In another embodiment, theneurological disorder is neuropathic pain. In another embodiment, theneuropathic pain is diabetic neuropathy.

In one embodiment, the neurological disorder is a neurodegenerativedisease. In one embodiment, the neurodegenerative disease is Parkinson'sdisease. In another embodiment, the neurodegenerative disorder isAlzheimer's disease.

In one embodiment, the compounds described herein treat, prevent, and/ormanage a neurological disorder of the central nervous system, withoutcausing addiction to said compounds.

Any suitable route of administration can be employed for providing thepatient with a therapeutically or prophylactically effective dose of anactive ingredient. For example, oral, mucosal (e.g., nasal, sublingual,buccal, rectal, vaginal), parenteral (e.g., intravenous, intramuscular),transdermal, and subcutaneous routes can be employed. Exemplary routesof administration include oral, transdermal, and mucosal. Suitabledosage forms for such routes include, but are not limited to,transdermal patches, ophthalmic solutions, sprays, and aerosols.Transdermal compositions can also take the form of creams, lotions,and/or emulsions, which can be included in an appropriate adhesive forapplication to the skin or can be included in a transdermal patch of thematrix or reservoir type as are conventional in the art for thispurpose. An exemplary transdermal dosage form is a “reservoir type” or“matrix type” patch, which is applied to the skin and worn for aspecific period of time to permit the penetration of a desired amount ofactive ingredient. The patch can be replaced with a fresh patch whennecessary to provide constant administration of the active ingredient tothe patient.

The amount to be administered to a patient to treat, prevent, and/ormanage the disorders described herein will depend upon a variety offactors including the activity of the particular compound employed, orthe ester, salt or amide thereof, the route of administration, the timeof administration, the rate of excretion or metabolism of the particularcompound being employed, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount required. For example, thephysician or veterinarian could start doses of the compounds employed atlevels lower than that required in order to achieve the desiredtherapeutic effect and gradually increase the dosage until the desiredeffect is achieved.

In general, a suitable daily dose of a compound provided herein will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic or prophylactic effect. Such an effective dosewill generally depend upon the factors described above. Generally, oral,intravenous, intracerebroventricular and subcutaneous doses of thecompounds provided herein for a patient will range from about 0.005 mgper kilogram to about 5 mg per kilogram of body weight per day. In oneembodiment, the oral dose of a compound provided herein will range fromabout 10 mg to about 300 mg per day. In another embodiment, the oraldose of a compound provided herein will range from about 20 mg to about250 mg per day. In another embodiment, the oral dose of a compoundprovided herein will range from about 100 mg to about 300 mg per day. Inanother embodiment, the oral dose of a compound provided herein willrange from about 10 mg to about 100 mg per day. In another embodiment,the oral dose of a compound provided herein will range from about 25 mgto about 50 mg per day. In another embodiment, the oral dose of acompound provided herein will range from about 50 mg to about 200 mg perday. Each of the above-recited dosage ranges may be formulated as asingle or multiple unit dosage formulations.

In some embodiments, the compounds disclosed herein may be used incombination with one or more second active agents to treat, prevent,and/or manage disorders described herein.

3. Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms provided herein comprise a compound provided herein, or apharmaceutically acceptable salt, stereoisomer, clathrate, or prodrugthereof. Pharmaceutical compositions and dosage forms can furthercomprise one or more excipients.

Pharmaceutical compositions and dosage forms provided herein can alsocomprise one or more additional active ingredients. Examples of optionalsecond, or additional, active ingredients are also disclosed herein.

Single unit dosage forms provided herein are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintra-arterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage foams suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms will typically varydepending on their use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms are used will vary fromone another and will be readily apparent to those skilled in the art.See, e.g., Remington's Pharmaceutical Sciences, 18th Ed., MackPublishing, Easton Pa. (1990).

In one embodiment, pharmaceutical compositions and dosage forms compriseone or more excipients. Suitable excipients are well known to thoseskilled in the art of pharmacy, and non-limiting examples of suitableexcipients are provided herein. Whether a particular excipient issuitable for incorporation into a pharmaceutical composition or dosageform depends on a variety of factors well known in the art including,but not limited to, the way in which the dosage form will beadministered to a patient. For example, oral dosage forms such astablets may contain excipients not suited for use in parenteral dosageforms. The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients may be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines are particularly susceptibleto such accelerated decomposition. Consequently, provided arepharmaceutical compositions and dosage forms that contain little, ifany, lactose other mono- or disaccharides. As used herein, the term“lactose-free” means that the amount of lactose present, if any, isinsufficient to substantially increase the degradation rate of an activeingredient.

Lactose-free compositions can comprise excipients that are well known inthe art and are listed, for example, in the U.S. Pharmacopeia (USP)25-NF20 (2002). In general, lactose-free compositions comprise activeingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. In one embodiment,lactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and/or magnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms can be preparedusing anhydrous or low moisture containing ingredients and low moistureor low humidity conditions. Pharmaceutical compositions and dosage formsthat comprise lactose and at least one active ingredient that comprisesa primary or secondary amine are preferably anhydrous if substantialcontact with moisture and/or humidity during manufacturing, packaging,and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are, in one embodiment, packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g., vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. In one embodiment, dosage forms comprise a compoundprovided herein in an amount of from about 0.10 to about 500 mg. Inother embodiments, dosage forms comprise a compound provided herein inan amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50,100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.

In other embodiments, dosage forms comprise a second active ingredientin an amount of 1 to about 1000 mg, from about 5 to about 500 mg, fromabout 10 to about 350 mg, or from about 50 to about 200 mg. Of course,the specific amount of the second active agent will depend on thespecific agent used, the diseases or disorders being treated or managed,and the amount(s) of a compound provided herein, and any optionaladditional active agents concurrently administered to the patient.

(a) Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administrationcan be provided as discrete dosage forms, such as, but not limited to,tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g.,flavored syrups). Such dosage forms contain predetermined amounts ofactive ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington's TheScience and Practice of Pharmacy, 21st Ed., Lippincott Williams &Wilkins (2005).

Oral dosage forms provided herein are prepared by combining the activeingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

In one embodiment, oral dosage forms are tablets or capsules, in whichcase solid excipients are employed. In another embodiment, tablets canbe coated by standard aqueous or non-aqueous techniques. Such dosageforms can be prepared by any of the methods of pharmacy. In general,pharmaceutical compositions and dosage forms are prepared by uniformlyand intimately admixing the active ingredients with liquid carriers,finely divided solid carriers, or both, and then shaping the productinto the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants. Binders suitable for use in pharmaceutical compositionsand dosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Aspecific example of a binder is a mixture of microcrystalline celluloseand sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitableanhydrous or low moisture excipients or additives include AVICEL-PH-103™and Starch 1500 LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions is, in oneembodiment, present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants may be used in the compositions to provide tablets thatdisintegrate when exposed to an aqueous environment. Tablets thatcontain too much disintegrant may disintegrate in storage, while thosethat contain too little may not disintegrate at a desired rate or underthe desired conditions. Thus, a sufficient amount of disintegrant thatis neither too much nor too little to detrimentally alter the release ofthe active ingredients may be used to form solid oral dosage forms. Theamount of disintegrant used varies based upon the type of formulation,and is readily discernible to those of ordinary skill in the art. In oneembodiment, pharmaceutical compositions comprise from about 0.5 to about15 weight percent of disintegrant, or from about 1 to about 5 weightpercent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, agar-agar, alginic acid, calciumcarbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, for example, a syloid silica gel(AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPlano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants may be used in an amount of less than about 1 weight percentof the pharmaceutical compositions or dosage forms into which they areincorporated.

In one embodiment, a solid oral dosage form comprises a compoundprovided herein, and optional excipients, such as anhydrous lactose,microcrystalline cellulose, polyvinylpyrrolidone, stearic acid,colloidal anhydrous silica, and gelatin.

(b) Controlled Release Dosage Forms

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active agents provided herein. In one embodiment, provided aresingle unit dosage forms suitable for oral administration such as, butnot limited to, tablets, capsules, gelcaps, and caplets that are adaptedfor controlled-release.

In one embodiment, controlled-release pharmaceutical products improvedrug therapy over that achieved by their non-controlled counterparts. Inanother embodiment, the use of a controlled-release preparation inmedical treatment is characterized by a minimum of drug substance beingemployed to cure or control the condition in a minimum amount of time.Advantages of controlled-release formulations include extended activityof the drug, reduced dosage frequency, and increased patient compliance.In addition, controlled-release formulations can be used to affect thetime of onset of action or other characteristics, such as blood levelsof the drug, and can thus affect the occurrence of side (e.g., adverse)effects.

In another embodiment, the controlled-release formulations are designedto initially release an amount of drug (active ingredient) that promptlyproduces the desired therapeutic or prophylactic effect, and graduallyand continually release of other amounts of drug to maintain this levelof therapeutic or prophylactic effect over an extended period of time.In one embodiment, in order to maintain a constant level of drug in thebody, the drug can be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled-release of an active ingredient can be stimulated by variousconditions including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

(c) Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intra-arterial. In someembodiments, administration of a parenteral dosage form bypassespatients' natural defenses against contaminants, and thus, in theseembodiments, parenteral dosage forms are sterile or capable of beingsterilized prior to administration to a patient. Examples of parenteraldosage forms include, but are not limited to, solutions ready forinjection, dry products ready to be dissolved or suspended in apharmaceutically acceptable vehicle for injection, suspensions ready forinjection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butnot limited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water-miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodextrin and its derivativescan be used to increase the solubility of a compound provided herein.See, e.g., U.S. Pat. No. 5,134,127, which is incorporated herein byreference.

(d) Topical and Mucosal Dosage Forms

Topical and mucosal dosage forms provided herein include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington's The Science and Practice ofPharmacy, 21st Ed., Lippincott Williams & Wilkins (2005); andIntroduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedherein are well known to those skilled in the pharmaceutical arts, anddepend on the particular tissue to which a given pharmaceuticalcomposition or dosage form will be applied. In one embodiment,excipients include, but are not limited to, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to formsolutions, emulsions or gels, which are non-toxic and pharmaceuticallyacceptable. Moisturizers or humectants can also be added topharmaceutical compositions and dosage forms. Examples of additionalingredients are well known in the art. See, e.g., Remington's TheScience and Practice of Pharmacy, 21st Ed., Lippincott Williams &Wilkins (2005).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients. Also,the polarity of a solvent carrier, its ionic strength, or tonicity canbe adjusted to improve delivery. Compounds such as stearates can also beadded to pharmaceutical compositions or dosage forms to alter thehydrophilicity or lipophilicity of one or more active ingredients so asto improve delivery. In other embodiments, stearates can serve as alipid vehicle for the formulation, as an emulsifying agent orsurfactant, or as a delivery-enhancing or penetration-enhancing agent.In other embodiments, salts, solvates, prodrugs, clathrates, orstereoisomers of the active ingredients can be used to further adjustthe properties of the resulting composition.

4. Kits

In one embodiment, active ingredients provided herein are notadministered to a patient at the same time or by the same route ofadministration. In another embodiment, provided are kits which cansimplify the administration of appropriate amounts of activeingredients.

In one embodiment, a kit comprises a dosage form of a compound providedherein. Kits can further comprise one or more second active ingredientsas described herein, or a pharmacologically active mutant or derivativethereof, or a combination thereof.

In other embodiments, kits can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits can further comprise cells or blood for transplantation as well aspharmaceutically acceptable vehicles that can be used to administer oneor more active ingredients. For example, if an active ingredient isprovided in a solid form that must be reconstituted for parenteraladministration, the kit can comprise a sealed container of a suitablevehicle in which the active ingredient can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

VI. EXAMPLES

Certain embodiments are illustrated by the following non-limitingexamples.

A. General Procedures for Compound Synthesis

In the examples below, unless otherwise indicated, all temperatures areset forth in degrees Celsius and all parts and percentages are byweight. Reagents may be purchased from commercial suppliers, such asSigma-Aldrich® Chemical Company, and may be used without furtherpurification unless otherwise indicated. Reagents may also be preparedfollowing standard literature procedures known to those skilled in theart. Solvents may be purchased from Sigma-Aldrich® in Sure-Seal® bottlesand used as received. All solvents may be purified using standardmethods known to those skilled in the art, unless otherwise indicated.

The reactions set forth below were done generally at ambienttemperature, unless otherwise indicated. Unless otherwise specified,generally the reaction flasks were fitted with rubber septa forintroduction of substrates and reagents via syringe. Analytical thinlayer chromatography (TLC) was performed using glass-backed silica gelpre-coated plates and eluted with appropriate solvent ratios (v/v).Reactions were assayed by TLC or LCMS, and terminated as judged by theconsumption of starting material. Visualization of the TLC plates wasdone with UV light (254 wavelength) or with an appropriate TLCvisualizing solvent, such as basic aqueous KMnO₄ solution activated withheat. Flash column chromatography (see, e.g., Still et al., J. Org.Chem., 43: 2923 (1978)) was performed using, for example, silica gel 60or various MPLC systems (such as Biotage® or ISCO® separation systems).

The compound structures in the examples below were confirmed by one ormore of the following methods: proton nuclear magnetic resonancespectroscopy, mass spectroscopy, elemental microanalysis, and meltingpoint. Proton nuclear magnetic resonance (¹H NMR) spectra weredetermined using a NMR spectrometer operating at a certain fieldstrength. Chemical shifts are reported in parts per million (ppm, δ)downfield from an internal standard, such as TMS. Alternatively, ¹H NMRspectra were referenced to signals from residual protons in deuteratedsolvents, for example, as follows: CDCl₃=7.25 ppm; DMSO-d₆=2.49 ppm;C₆D₆=7.16 ppm; CD₃OD=3.30 ppm. Peak multiplicities are designated, forexample, as follows: s, singlet; d, doublet; dd, doublet of doublets; t,triplet; dt, doublet of triplets; q, quartet; br, broadened; and m,multiplet. Coupling constants are given in Hertz (Hz). Mass spectra (MS)data were obtained using a mass spectrometer with APCI or ESIionization.

1. General Procedure A

(a) Synthesis of 2-(5-ethylthiophen-2-yl)ethanol

To a solution of 2-ethylthiophene (2 g, 17.85 mmol, 1 eq) in anhydrousdiethyl ether at 0° C. was added n-BuLi (8.6 mL, 21.4 mmol, 2.5 M inhexanes, 1.2 eq) over 15 minutes. The mixture was stirred at roomtemperature for 30 minutes. After cooling to 0° C., a solution ofethylene oxide (1.1 mL, 21.4 mmol, 1.2 eq) in anhydrous ether was added.After stirring at 0° C. for 3 hr, the reaction mixture was quenched withwater and extracted with diethyl ether. The organic layer was dried overNa₂SO₄ and concentrated to give a crude product. The crude product waspurified by column chromatography.

(b) Synthesis of(2-ethyl-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

To a solution of 2-(5-ethylthiophen-2-yl)ethanol (1 g, 6.4 mmol, 1.1 eq)and aminoacetaldehyde dimethylacetal (612 mg, 5.83 mmol, 1 eq) was addedCF₃SO₃H (2.7 g, 17.5 mmol, 3 eq) dropwise at 0° C. After stirring atroom temperature overnight, the reaction mixture was diluted with water,adjusted pH to ˜8 with Na₂CO₃, and extracted with EtOAc. The organiclayer was dried over Na₂SO₄, and concentrated. The crude product waspurified by column chromatography.

(c) Synthesis of the HCl salt of(2-ethyl-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

A solution of(2-ethyl-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine in MTBE wastreated with gaseous HCl at 0° C. for 10 minutes. The precipitatedproduct was collected by vacuum filtration and dried to give the desiredproduct.

2. General Procedure B

2-(Thiophen-3-yl)ethanol (7.5 mmol), amino acetal (11.25 mmol) andtriflic acid (1.70 mL, 15 mmol) were combined in 7.5 mL 1,4-dioxane(anhydrous). The blackish solution was stirred at room temperature for 2hr, and then poured slowly into saturated aqueous K₂CO₃ solution. Thesolution was washed with EtOAc (3×50 mL) and the combined EtOAc washeswere washed with brine, dried (Na₂SO₄), filtered and concentrated. Thecrude product was dissolved in MeOH and 4M HCl in dioxane (10 mL) wasadded. The solution was concentrated to ˜4 mL and MTBE was added (30mL). The solution was sonicated and the tan precipitate was filtered,washed with MTBE and dried in vacuo.

3. General Procedure C

To 3-(thiophen-2-yl)propan-1-ol (1 g, 7.0 mmol) and amino acetal (0.84g, 7.0 mmol) in 1,4-dioxane in a microwave vial was added CF₃SO₃H (0.8mL, 7.0 mmol). The reaction vessel was sealed and heated in a microwavereactor at 110° C. for 15 min at which time the mixture was cooled, madebasic with 10% KOH (aq.) and the aqueous layer was extracted with EtOAc(3×50 mL). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and the solvent removed in vacuo to afford thecrude product mixed with uncyclized side-product. The combined brownliquid was Boc-protected following standard protocols and purified byflash column chromatography (0-50% EtOAc in hexanes) to afford a mixtureof uncyclized and cyclized product. The desired 7-membered ring compoundwas isolated by RP-HPLC (0.1% aqueous NH₄HCO₃ in acetonitrile).

4. General Procedure D

(a) Synthesis of 2-(2-bromothiophen-3-yl)ethanol

NBS (0.58 g, 3.3 mmol) was added to 2-(thiophen-3-yl)ethanol (0.4 g, 3.1mmol) in CHCl₃:AcOH (1:1 v/v; 9 mL) at 0° C. and the resulting mixturewas stirred at 0° C. for 1 hr at which time the reaction mixture wasdiluted with NaHCO₃ (sat. aq.) and extracted with EtOAc (3×50 mL). Thecombined organic fractions were washed with brine, dried over Na₂SO₄,filtered, and the solvent was removed in vacuo. The residue was purifiedby flash column chromatography (0-50% EtOAc in hexanes) to affordregiopure bromothiophene.

(b) Synthesis of(1-bromo-6,7-dihydro-4H-thieno[3,4-c]pyran-4-yl)methanamine

Bromothiophene (0.31 g, 1.5 mmol) and aminoacetaldehyde diethyl acetal(0.3 g, 2.25 mmol) were combined with 1,4-dioxane (2 mL). CF₃SO₃H (0.45g, 3.0 mmol) was added and the reaction mixture was stirred at 22° C.for 2 hr at which time the mixture was made basic with 10% KOH (aq.) andthe aqueous layer was extracted with EtOAc (3×50 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andthe solvent removed in vacuo to afford the crude amine product.

Boc-protection was performed following standard protocols.

(c) Synthesis of (6,7-dihydro-4H-thieno[3,4-c]pyran-4-yl)methanamine

To the purified Boc-protected bromothiophene (0.16 g, 0.45 mmol) in THF(16 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 0.4 mL, 1.0 mmol)and the resulting mixture was stirred at −78° C. for 2 hr at which timeMeOH (2 mL) was added and the reaction was allowed to warm to about 22°C. The solvent was removed and then the residue was redissolved in MeOHfor purification by RP-HPLC (0.1% aqueous NH₄HCO₃ in acetonitrile). TheBoc-protected material was then deprotected using HCl (4.0 M in1,4-dioxane, 5 mL) and the resulting HCl salt was precipitated with MTBE(50 mL) filtered and isolated as a white powder.

5. General Procedure E

(a) Synthesis of4-hydroxy-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carbonitrile

To 6,7-dihydrobenzo[b]thiophen-4(5H)-one (0.5 g, 3.3 mmol) andtrimethylamino N-oxide (0.074 g, 0.99 mmol) in CH₂Cl₂ (4 mL) was addedTMSCN dropwise. The resulting mixture was stirred at 22° C. for 16 hr atwhich time the entire mixture was deposited on a silica gel column.Purification with flash column chromatography (0-50% EtOAc in hexanes)afforded the desired cyanohydrin compound.

(b) Synthesis of 4-(aminomethyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ol

To the cyanohydrin compound (0.59 g, 3.3 mmol) in THF (6.5 mL) at 0° C.was added LAH (1.0 M THF, 6.5 mL). The resulting mixture was stirred at0° C. for 2 hr at which time the reaction mixture was poured into asaturated aqueous solution of K₂CO₃ and extracted with EtOAc (3×50 mL).The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and the solvent removed in vacuo to afford the desired aminoalcohol which was further purified by RP-HPLC (0.1% aqueous formic acidin acetonitrile). The solvent was removed in vacuo to afford the formicacid salt.

6. General Procedure F

(a) Synthesis of 4-(chloromethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran

The title compound was synthesized from 2-(thiophen-2-yl) ethanol andchloroacetaldehyde diethyl acetal according to General Procedure A.

(b) Synthesis of1-((6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methyl)pyrrolidine

A mixture of 4-(chloromethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran (1 g,5.305 mmol, 1 eq), pyrrolidine (11.3 g, 159.1 mmol, 30 eq) and NaI (50mg) in DMF (50 mL) in a sealed tube was stirred at 130° C. for 6 hr. Thereaction mixture was cooled and poured into H₂O and the pH was adjustedto ˜2 with 2N HCl. The resulting solution was washed with EtOAc. Theaqueous layer was then adjusted to pH 9-10 and extracted with EtOAc. TheEtOAc layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The resulting crude product was purified by preparativeHPLC. After removal of organic volatiles of the collected HPLCfractions, the pH of remaining aqueous phase was adjusted to ˜8 withsaturated Na₂CO₃ solution. The aqueous solution was extracted with EtOAc(3 times). The combined EtOAc extract was washed with brine, dried withNa₂SO₄, and concentrated to give the desired product.

7. General Procedure G

(a) Synthesis oftert-butyl(2-(5-fluorothiophen-2-yl)ethoxy)dimethylsilane

To 2-thiophene-2-ethanol (1.28 g, 10 mmol) in CH₂Cl₂ (12 mL) was addedTBSCl (1.66 g, 11 mmol) followed by imidazole (1.36 g, 20 mmol) and theresulting cloudy mixture was stirred for 1 hr at 22° C. Upon reactioncompletion, the mixture was diluted with NH₄Cl (sat. aq.) and theaqueous phase was extracted with EtOAc (3×50 mL). The combined organiclayers were washed with NaHCO₃ (sat. aq.), brine, dried over Na₂SO₄,filtered and the solvent removed in vacuo to afford the crude protectedalcohol which was used in the next step without further purification.

(b) Synthesis of(2-fluoro-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

To the silyl protected 2-(thiophen-2-yl)ethanol (0.96 g, 4.0 mmol) indry Et₂O (20 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 2.38 mL)and the resulting yellow solution was stirred at −78° C. for 3 hr atwhich time NFSI (2.5 g, 7.9 mmol) was added and the mixture was allowedto warm to 22° C. over 3 hr. The product formation was monitored byGC-MS. When no more product was formed, the reaction was quenched withMeOH and the solvent removed in vacuo. Purification by flash columnchromatography (0 to 50% EtOAc in hexanes) afforded a mixture of thefluorinated and non-fluorinated TB S-protected ethanols which were takenon to the next step without further purification.

Cyclization in the presence of CF₃SO₃H was performed following theGeneral Procedure A. Upon isolation of the fluorinated andnon-fluorinated mixture of amino pyrans, the amine functionality wasprotected with Boc₂O in the presence of 10% NEt₃ in methanol.Purification by flash column chromatography (0 to 30% EtOAc in hexanes)afforded a mixture of the fluorinated and non-fluorinated products whichwere submitted to further purification by RP-HPLC (0.1% aqueous formicacid in acetonitrile) to provide the pure fluorinated analog. TheBoc-protecting group on the purified fluorinated analog was removedusing standard procedure to give the corresponding amine.

8. General Procedure H

(a) Synthesis of tert-butyl(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamate

A solution of (6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine (6.3g, 37.3 mmol, 1 eq), Boc₂O (8.9 g, 40.8 mmol, 1.1 eq), and DMAP (10 mg)in THF (50 mL) was stirred at room temperature for 1 hr. The mixture wasconcentrated and purified by column chromatography to give the desiredproduct.

(b) Synthesis of tert-butyl(2-iodo-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamate

A solution of tert-butyl(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamate (2.9 g, 1.3mmol, 1 eq), NIS (5.2 g, 2.2 mmol, 2 eq), and AcOH (3 mL) in CHCl₃ (50mL) was stirred at room temperature for 7 hr. The reaction mixture wasneutralized with triethyl amine, concentrated, and diluted with water.The mixture was extracted with n-hexane. The organic phase was driedover Na₂SO₄, concentrated, and purified by column chromatography to givethe desired product (3 g).

(c) Synthesis of(2-(piperidin-1-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

A mixture of tert-butyl(2-iodo-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-methylcarbamate (400 mg,1.0 mmol, 1 eq), piperidine (2 mL), Cu metal (6.4 mg, 1 mmol, 0.1 eq),and K₃PO₄.3H₂O (539.3 mg, 2.34 mmol, 2.3 eq) in 2-dimethylamino-ethanol(deanol) (5 mL) was stirred at 85° C. in a sealed tube for 28 hr. Aftercooling to room temperature, the reaction mixture was diluted withwater, extracted with ethyl acetate, washed with brine, dried overNa₂SO₄, concentrated and purified by Al₂O₃ column chromatography. TheBoc protecting group was removed with HCl under standard conditions togive the product(2-(piperidin-1-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine.

9. General Procedure I

(a) Synthesis of 2-(4-bromothiophen-2-yl)ethanol

To a solution of 2,4-dibromothiophene (1 g, 4.13 mmol) in anhydrousether was added n-BuLi (1.66 mL, 4.13 mmol) at −78° C. dropwise. Afterstirring at −78° C. for 0.5 hr, oxirane (0.32 mL, 19.28 mmol/mL inether) was added to the reaction mixture quickly. After stirring at 0°C. for 1.5 hr, the reaction mixture was quenched with aqueous NH₄Clsolution, extracted with EtOAc, concentrated and purified to give thedesired product.

(b) Synthesis of(3-bromo-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

The title compound was synthesized from 2-(4-bromothiophen-2-yl)ethanoland amino-acetaldehyde dimethylacetal according to General Procedure A.

(c) Synthesis of tert-butyl(3-bromo-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamate

The title compound was synthesized from(3-bromo-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine according toGeneral Procedure H.

(d) Synthesis of tert-butyl(3-(pyridin-3-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamate

The title compound was synthesized from tert-butyl(3-bromo-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamateaccording to General Procedure J.

(e) Synthesis of HCl salt of(3-(pyridin-3-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

The title compound was synthesized from tert-butyl(3-(pyridin-3-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamate according to General Procedure J(e).

10. General Procedure J

(a) Synthesis of 2-(5-bromothiophen-2-yl)ethanol

To a solution of 2-(thiophen-2-yl)ethanol (3 g, 23.4 mmol, 1 eq) andHOAc (5 mL) in CHCl₃ was added NBS in portions at room temperature.After stirring at room temperature overnight, the reaction mixture waspoured into water and extracted with CHCl₃ twice. The combined organiclayer was dried over Na₂SO₄, concentrated and purified by columnchromatography to give the desired product.

(b) Synthesis of(2-bromo-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

The title compound was synthesized from 2-(5-bromothiophen-2-yl)ethanoland aminoacetaldehyde dimethylacetal according to General Procedure A.

(c) Synthesis of tert-butyl(2-bromo-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamate

The title compound was synthesized from(2-bromo-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine according toGeneral Procedure H.

(d) Synthesis of tert-butyl(2-(pyridin-3-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamate

A mixture of tert-butyl(2-bromo-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamate (500 mg,1.44 mmol), pyridine-3-boronic acid (351 mg, 2.88 mmol), Pd(OAc)₂ (33mg), PPh₃ (170 mg, 0.65 mmol) in 1,4-dioxane was purged with nitrogen.After stirring at room temperature for 0.5 hr, 457 mg of Na₂CO₃ in 3 mLof H₂O was added. The reaction mixture was stirred at 100° C. for 2 hr.After cooling to room temperature, the reaction mixture was poured into100 mL of water and extracted with EtOAc twice. The combined organiclayers were washed with brine, dried over Na₂SO₄, concentrated andpurified by column chromatography to give the desired product.

(e) Synthesis of the HCl salt of(2-(pyridin-3-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

To a solution of tert-butyl(2-(pyridin-3-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamatein MeOH was added an HCl solution (10 mL, 5 N in MeOH). The mixture wasstirred at room temperature for 0.5 h, and a solid precipitated. Thesolid was collected by vacuum filtration and washed with EtOAc to givethe desired product.

11. General Procedure K

tert-Butyl(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamate (1.96mmol) was dissolved in anhydrous DMF (20 mL) and cooled to 0° C. NaH(60% dispersion in mineral oil, 86 mg, 2.15 mmol) was added in oneportion and the resulting orange suspension was stirred for 30 min.Deuterated methyl iodide (133 μL, 2.15 mmol) was added and the resultingmixture was stirred over the two to three days. After about 65 hr, themixture was poured into H₂O (30 mL) and washed with Et₂O (2×30 mL). Theaqueous phase was extracted with EtOAc (1×20 mL) and the organic phaseswere combined, washed with brine, dried (Na₂SO₄), filtered, andconcentrated. The crude material was purified by flash columnchromatography on a Biotage system (eluting with 0 to 50% EtOAc inhexanes gradient) to give the desired Boc-protected material.

The BOC protected material (340 mg, 1.04 mmol) was dissolved in MTBE (10mL) and HCl in dioxane was added (4 M, 1.5 mL). The resulting solutionwas stirred for 2 days, then poured into saturated aqueous Na₂CO₃ (30mL) and washed with EtOAc (3×40 mL). The combined organic phases werewashed with brine, dried (Na₂SO₄), filtered, and concentrated. The crudeN-deutero methyl compound was dissolved in MTBE (10 mL) and HCl indioxane (4 M, 454 μL, 1.04 eq) was added. The resulting off-whiteprecipitate was collected by filtration, and washed with MTBE, thendried in vacuo to give the pure HCl salt of the deuterated product.

12. General Procedure L

The above iodothienyl compound (0.22 g, 0.55 mmol, prepared usingGeneral Procedure H), methyl-2,2-difluoro-2-(fluorosulfonyl)acetate(0.21 g, 1.1 mmol) and CuBr.Me₂S (0.023 g, 0.11 mmol) were combined withanhydrous DMF (5 mL) in a sealed microwave vial. The resulting mixturewas heated in a microwave reactor for 10 min at 90° C. The reaction wasdetermined by LC-MS to be 5% complete. The reaction mixture wasre-subjected to the microwave reactor at 100° C. for 40 min at whichtime the reaction was determined by LC-MS to be 95% complete. Thereaction mixture was diluted with Et₂O (50 mL) and the organic layer waswashed with NaHCO₃ (sat. aq.) and then brine, dried with Na₂SO₄,filtered, and concentrated in vacuo to afford the crude trifluoromethylproduct. Purification with flash column chromatography (0-50% EtOAc inhexanes) afforded pure trifluoromethyl product which was thendeprotected using HCl (4 M in 1,4-dioxane, 5 mL), and the resulting HClsalt was precipitated with MTBE (50 mL), filtered, and isolated as awhite powder.

13. General Procedure M

(a) Synthesis of 4,5,6,7-tetrahydrobenzo[b]thiophene-4-carbonitrile

To a solution of the above cyclic ketone (1.0 g, 6.6 mmol) in MeOH (330mL) and DMSO (10 mL) was added Tosmic (1.7 g, 8.7 mmol) followed byKOtBu (2.5 g, 26.3 mmol) in small portions. The resulting mixture wasstirred at 25° C. for 36 hr at which time the bulk of the volatiles wereremoved in vacuo. The reaction mixture was diluted with EtOAc and H₂O.The organics were washed with NH₄Cl (sat. aq.), brine, dried overNa₂SO₄, concentrated and purified by column chromatography (0 to 30%EtOAc in hexanes) to give the desired nitrile compound.

(b) Synthesis of (4,5,6,7-tetrahydrobenzo[b]thiophen-4-yl)methanamine

The resulting nitrile (0.3 g, 1.8 mmol) was reduced to the primary amineusing excess BH₃.THF (10 mL, 10 mmol) diluted to 20 mL with 10 mLadditional THF. The reaction mixture was stirred at 25° C. for 1 hr atwhich time careful addition of K₂CO₃ (sat. aq.) was used to quench thereaction. EtOAc was added and the organic layer was washed with NaHCO₃and brine, dried over Na₂SO₄, and filtered. The resulting yellow oil wasfurther purified by RP-HPLC to afford the primary amine compound.

(c) Synthesis ofN-methyl-1-(4,5,6,7-tetrahydrobenzo[b]thiophen-4-yl)methanamine

The primary amine was protected with excess BOC₂O in a solution of 10%NEt₃ in MeOH. The reaction mixture was stirred at 25° C. for 1 hr atwhich time all volatiles were removed in vacuo. The crude material wastaken up in 10 mL THF. 20 mL 1M LAH in THF was added dropwise, and thereaction mixture was stirred at 25° C. for 2 hr at which time carefuladdition of K₂CO₃ (sat. aq.) was used to quench the reaction. EtOAc wasadded and the organic layer was washed with NaHCO₃, dried with brine,dried over Na₂SO₄, and filtered. The resulting yellow oil was furtherpurified by RP-HPLC to afford the secondary amine compound.

14. General Procedure N

(a) Synthesis of (S)-(9H-fluoren-9-yl)methyl1-hydroxy-3-methylbutan-2-yl(methyl)carbamate

To a mixture of (S)-2-aminopropan-1-ol (2 g, 26.6 mmol) and Na₂CO₃ (5.6g, 53.2 mmol) in 1,4-dioxane and water (25 mL/25 mL) at 0° C. was addedFmocCl (10.2 g, 39.9 mmol) and the resulting mixture was then warmed toroom temperature gradually. After the amine was consumed completely asindicated by TLC, water (25 mL) was added. The mixture was extractedwith DCM (3×50 mL). The organic phase was washed with brine (50 mL), anddried over anhydrous Na₂SO₄. After filtration and concentration, thecrude product was purified by column chromatography to give the titlecompound (7.1 g, 90%).

(b) Synthesis of (S)-(9H-fluoren-9-yl)methylmethyl(3-methyl-1-oxobutan-2-yl)carbamate

To a solution of oxalyl chloride (1.89 g, 15.0 mmol) in dry DCM (10 mL)at −65° C. was added DMSO (1.2 g, 15.0 mmol) in dry DCM (10 mL)dropwise. After stirring for 30 min, N-Fmoc (S)-2-aminopropan-1-ol (3.0g, 10.0 mmol) in dry DCM (20 mL) was added dropwise. After stirring for2 hr, Et₃N (3.0 g, 30 mmol) was added dropwise and the mixture was thenwarmed to room temperature gradually. The reaction mixture was treatedwith water, extracted with DCM (3×100 mL). The organic extract waswashed with brine, and dried over anhydrous Na₂SO₄. After filtration,the solvent was removed under reduced pressure to give the titlecompound (2.8 g, 94.9%).

(c) Synthesis of (S)-(9H-fluoren-9-yl)methyl1-(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-2-methylpropyl(methyl)carbamate

The title compound was synthesized from (S)-(9H-fluoren-9-yl)methylmethyl(3-methyl-1-oxobutan-2-yl)carbamate according to General ProcedureA. Diastereomeric products were separated by RP-HPLC at this stage.

-   -   (d) Synthesis of        (S)-1-((S)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)ethanamine

To a solution of (9H-fluoren-9-yl)methyl(S)-1-((S)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)ethylcarbamate (885mg, 3.0 mmol) in CH₃CN (10 mL) at 0° C. was added piperidine (382 mg,4.5 mmol) dropwise. After stirring overnight, the reaction solution wasconcentrated under reduced pressure and the residue was purified bycolumn chromatography to give the title compound (450 mg, 82%).

(e) Synthesis of the HCl salt of(S)-1-((S)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)ethanamine

A solution of(S)-1-((S)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)ethanamine (450 mg,2.5 mmol) in ether (50 mL) was treated with gaseous HCl at 0° C. for 10minutes. The precipitated solid was collected by vacuum filtration anddried to give the title product (460 mg, 84%).

15. General Procedure O

(a) Synthesis of methyl 1-amino cyclohexanecarboxylate

To MeOH (50 mL) was added SOCl₂ (8.8 g, 75.1 mmol) dropwise at 0° C.,followed by the addition of 1-aminocyclopropanecarboxylic acid (5.0 g,49.8 mmol) in one portion. The resulting mixture was refluxed for 1 to 3h. The reaction solution was concentrated under reduced pressure to givea salt of the title compound (5.8 g, 100%).

(b) Synthesis of methyl1-(((9H-fluoren-9-yl)methoxy)carbonylamino)cyclohexanecarboxylate

To a mixture of methyl 1-aminocyclopropanecarboxylate (5.8 g, 50.4 mmol)and Na₂CO₃ (8.0 g, 74.6 mmol) in 1, 4-dioxane (50 mL) and water (50 mL)at 0° C. was added FmocCl (19.4 g, 75.2 mmol). The resulting mixture waswarmed gradually to room temperature. After the amine was consumedcompletely as indicated by TLC, water (50 mL) was added and the mixturewas extracted with DCM (3×60 mL). The DCM extract was washed with brine,and dried over anhydrous Na₂SO₄. After filtration and concentration, thecrude product was purified by column chromatography to give the titlecompound (15 g, 88%).

Synthesis of (9H-fluoren-9-yl)methyl1-(hydroxymethyl)cyclohexylcarbamate

To a solution of (9H-fluoren-9-yl)methyl1-(methoxycarbonyl)-cyclopropylcarbamate (15 g, 44.5 mmol) in THF (100mL) at −5° C. was added LiAlH₄ (1.0 g, 26.3 mmol) in portions. Afterstirring at room temperature for 3 h, water (10 mL) was added to quenchthe reaction. The mixture was filtered and the filtrate was extractedwith EtOAc (3×100 mL). The organic extract was washed with brine, anddried over anhydrous Na₂SO₄. After filtration and concentration, thecrude product was purified by column chromatography to give the titlecompound (12.3 g, 90%).

(c) Synthesis of (9H-fluoren-9-yl)methyl 1-formylcyclohexylcarbamate

The title compound was synthesized according to General Procedure N.

(d) Synthesis of (9H-fluoren-9-yl)methyl1-(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)cyclohexylcarbamate

The title compound was synthesized according to General Procedure A(b).

(e) Synthesis of1-(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)cyclohexanamine

The title compound was synthesized according to General Procedure N(d).

(f) Synthesis of ethyl1-(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)cyclohexylcarbamate

To a solution of1-(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-cyclopropanamine (1 g, 5.1mmol) and Et₃N (0.8 g, 7.5 mmol) in dry DCM (20 mL) at 0° C. was addedethyl chloroformate (0.8 g, 7.5 mmol) dropwise. After stirring at 0° C.for 4 h, water (20 mL) was added to quench the reaction. The mixture wasextracted with DCM (3×50 mL) and the organic extract was dried overanhydrous Na₂SO₄. After filtration and concentration, the crude productwas purified by column chromatography to give the title compound (1.1 g,83%).

(g) Synthesis of1-(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-N-methylcyclohexanamine

To a solution of ethyl1-(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)cyclopropylcarbamate (1.1 g,4.1 mmol) in dry THF (20 mL) at 0° C. under N₂ was added LiAlH₄ (152 mg,4.0 mmol) in one portion. The resulting mixture was refluxed for 2 h andthen cooled to room temperature. Water (5 mL) was added to quench thereaction. The reaction mixture was filtered and the filtrate wasextracted with EtOAc (3×75 mL). The combined extract was washed withbrine, and dried over anhydrous Na₂SO₄. After filtration andconcentration, the crude product was purified by column chromatographyto give the title compound (700 mg, 84%).

(h) Synthesis of the HCl salt of1-(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-N-methylcyclohexanamine

The title compound was synthesized according to General Procedure N.

16. General Procedure P

(a) Synthesis of 2-(4-methylthiophen-2-yl)ethanol

To a solution of 3-methylthiophene (5 g, 51.0 mmol) in dry ether (250mL) at −65° C. was added n-BuLi (25 mL, 2.5 N in THF) dropwise. Afterstirring for 1 h, oxirane (2.7 g, 61.3 mmol) was added in one portion.The resulting reaction mixture was warmed to room temperature andstirred overnight. The reaction was then quenched with water. Afterseparation of layers, the organic layer was washed with brine, and driedover anhydrous Na₂SO₄. After filtration and concentration, the crudeproduct was purified by column chromatography to give the title compound(6.2 g, 86%).

(b) Synthesis oftert-butyldimethyl(2-(4-methylthiophen-2-yl)ethoxy)silane

To a solution of 2-(4-methylthiophen-2-yl)ethanol (3.0 g, 21.1 mmol) anddiisopropylethylamine (4.1 g, 31.7 mmol) in dry DCM (50 mL) at 0° C. wasadded TBSCl (4.8 g, 32.0 mmol) in dry DCM (20 mL) dropwise and themixture was then warmed to room temperature gradually. After the alcoholwas consumed completely, water (10 mL) was added. The resulting mixturewas extracted with DCM (3×100 mL), washed with brine, and dried overanhydrous Na₂SO₄. After filtration and concentration, the crude productwas purified by column chromatography to give the title compound (5.1 g,94%).

(c) Synthesis oftert-butyl(2-(5-fluoro-4-methylthiophen-2-yl)ethoxy)dimethylsilane

To a solution of(2-(4-methylthiophen-2-yl)ethoxy)(tert-butyl)dimethylsilane (5.1 g, 19.9mmol) in dry THF (30 mL) at −5° C. was added LDA (20 mL in THF, 30 mmol)dropwise. After stirring for 1 h, NFSI (9.4 g, 29.8 mmol) in dry THF (10mL) was added dropwise and the resulting mixture was stirred for another2 h. The reaction was quenched with water (15 mL) and the resultingmixture was extracted with EtOAc (3×100 mL), washed with brine, anddried over anhydrous Na₂SO₄. After filtration and concentration, thecrude product was purified by column chromatography to give the titlecompound (3.7 g, 68%).

(d) Synthesis of(2-fluoro-3-methyl-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

The title compound was synthesized according to General Procedure A.

(e) Synthesis of the HCl salt of(2-fluoro-3-methyl-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

The title compound was synthesized according to General Procedure N.

17. General Procedure Q

(a) Synthesis of thiophene-3-carboxaldehyde

To a solution of 3-bromothiophene (0.65 g, 4.0 mmol) in anhydrous THF(20 mL) at −65° C. was added t-BuLi (3.5 mL, 8.8 mmol, 2.5 M in hexane)over 15 minutes. After stirring at −65° C. for 30 minutes, DMF (0.32 g,4.4 mmol) was added dropwise and the reaction was stirred at −65° C. for2 h. The reaction mixture was quenched with water and the mixture wasextracted with diethyl ether. The organic layer was dried over Na₂SO₄and concentrated to give a crude product. The crude product was purifiedby column chromatography to provide the title compound.

(b) Synthesis of ethyl 3-(thiophen-3-yl)acrylate

To a solution of thiophene-3-carbaldehyde (10 g, 89.3 mmol) in THF (500mL) at 0° C. was added ethyl (triphenylphosphoranylidene)acetate (35 g,100.5 mmol) in portions. After stirring overnight, the reaction mixturewas concentrated and purified by column chromatography to give the titlecompound (13.6 g, 83%).

(c) Synthesis of ethyl 4-nitro-3-(thiophen-3-yl)butanoate

To a solution of ethyl 3-(thiophen-3-yl)acrylate (5 g, 27.5 mmol) inCH₃NO₂ (20 mL) was added Triton B (5 mL) under N₂ and the resultingreaction mixture was refluxed overnight. The reaction mixture wasconcentrated and then diluted with water. The mixture was extracted withEtOAc, washed with brine, and dried over anhydrous Na₂SO₄. Afterfiltration and concentration, the crude product was purified by columnchromatography to give the title compound (4.3 g, 65%).

(d) Synthesis of 4-nitro-3-(thiophen-3-yl)butanoic acid

To a solution of ethyl 4-nitro-3-(thiophen-3-yl)butanoate (4.3 g, 18.2mmol) in MeOH (40 mL) at 0° C. was added 3 N aqueous NaOH (10 mL). Theresulting mixture was stirred at room temperature overnight. 2 N HCl wasthen added to adjust pH to 3˜4 followed by extraction with DCM. Theorganic extract was washed with brine and dried over anhydrous Na₂SO₄.After filtration, the solution was concentrated to give the titlecompound (3.4 g, 87%).

(e) Synthesis of 4,5-dihydro-4-(nitromethyl)cyclopenta[b]thiophen-6-one

To a solution of 4-nitro-3-(thiophen-3-yl)butanoic acid (3.4 g, 15.9mmol) in DCE (20 mL) was added PPA (20 g) and the resulting mixture wasrefluxed overnight. After concentration, the reaction mixture wastreated with solid NaOH, followed by addition of water. After stirringfor 30 minutes, the mixture was extracted with DCM. The DCM extract waswashed with brine and dried over anhydrous Na₂SO₄. After filtration andconcentration, the crude product was purified by column chromatographyto give the title compound (2.3 g, 74%).

(f) Synthesis of (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)methanamine

To a solution of 4,5-dihydro-4-(nitromethyl)cyclopenta[b]thiophen-6-one(2.3 g, 11.7 mmol) in dry THF (30 mL) at 0° C. was added LiAlH₄ (0.5 g13.1 mmol) in one portion. The resulting mixture was then refluxed for 4h. After cooling to room temperature, the reaction was quenched withwater and filtered. The filtrate was extracted with EtOAc, washed withbrine, and dried over anhydrous Na₂SO₄. After filtration andconcentration, the crude product was purified by column chromatographyto give the title compound (1.3 g, 72%).

(g) Synthesis of ethyl(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)methylcarbamate

The title compound was synthesized according to General Procedure O(g).

(h) Synthesis of1-(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-N-methylmethanamine

The title compound was synthesized according to General Procedure O(h).

(i) Synthesis of the HCl salt of1-(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-N-methylmethanamine

The title compound was synthesized according to General Procedure N(e).

18. General Procedure R

(a) Synthesis of triisopropyl(2-(thiophen-2-yl)ethoxy)silane

The title compound was synthesized according to General Procedure P.

(b) Synthesis of (2-(5-fluorothiophen-2-yl)ethoxy)triisopropylsilane

The title compound was synthesized according to General Procedure P.

(c) Synthesis of2′-fluoro-6′,7′-dihydrospiro[pyrrolidine-3,4′-thieno[3,2-c]pyran]

The title compound was synthesized according to General Procedure A.

(d) Synthesis of HCl salt of2′-fluoro-6′,7′-dihydrospiro[pyrrolidine-3,4′-thieno[3,2-c]pyran]

The title compound was synthesized according to General Procedure N.

19. General Procedure S

(a) Synthesis of tert-butyl3-hydroxy-3-(thiophen-3-yl)pyrrolidine-1-carboxylate

To a solution of 3-bromothiophene (10 g, 61.8 mmol) in dry ether (200mL) at −65° C. under N₂ was added n-BiLi dropwise. After stirring at−65° C. for 1 h, tert-butyl 3-oxopyrrolidine-1-carboxylate (13.7 g, 74.2mmol) in dry ether (80 mL) was added dropwise. After addition, thereaction mixture was warmed to 0° C. and stirred for 3 h. The reactionwas quenched with water and extracted with ether. The combined organiclayer was washed with brine, and dried over anhydrous Na₂SO₄. Afterfiltration and concentration, the crude product was purified by columnchromatography to give the title compound (9.8 g, 59%).

(b) Synthesis of tert-butyl3-(2-bromothiophen-3-yl)-3-hydroxypyrrolidine-1-carboxylate

To a solution of tert-butyl3-hydroxy-3-(thiophen-3-yl)pyrrolidine-1-carboxylate (5 g, 18.6 mmol) inAcOH (10 mL) and CHCl₃ (10 mL) at 0° C. was added NBS (5.0 g, 27.9 mmol)in portions. After stirring for 3 h, the reaction mixture was treatedwith Na₂SO₃ and water, followed by extraction with EtOAc. The combinedorganic layer was washed with brine, and dried over anhydrous Na₂SO₄.After filtration and concentration, the crude product was purified bycolumn chromatography to give the title compound (5.4 g, 84%).

(c) Synthesis of tert-butyl3-hydroxy-3-(2-(2-hydroxyphenyl)thiophen-3-yl)pyrrolidine-1-carboxylate

A mixture of tert-butyl3-(2-bromothiophen-3-yl)-3-hydroxypyrrolidine-1-carboxylate (5 g, 13.8mmol), Pd(OAc)₂ (31 mg, 0.14 mmol), Ph₃P (147 mg, 0.42 mmol),2-hydroxyphenylboronic acid (1.74 g, 27.6 mmol) and Na₂CO₃ (2.9 g, 27.6mmol) in dioxane (10 mL) and water (10 mL) was refluxed under N₂ for 3h. After the reaction was cooled to room temperature, the reactionmixture was extracted with EtOAc several times. The combined organiclayers were washed with brine, and dried over anhydrous Na₂SO₄. Afterfiltration and concentration, the crude product was purified by columnchromatography to give the title compound (4.4 g, 88%).

(d) Synthesis of tert-butylspiro[pyrrolidine-3,4′-thieno[3,2-c]chromene]-1-carboxylate

To a solution of tert-butyl3-hydroxy-3-(2-(2-hydroxyphenyl)thiophen-3-yl)pyrrolidine-1-carboxylate(4.4 g, 12.1 mmol) in DCM (25 mL) at 0° C. was added BF₃ (1.6 g, 24.2mmol) dropwise. After stirring overnight, the reaction mixture wastreated with water and extracted with EtOAc several times. The combinedorganic layer was washed with brine, and dried over anhydrous Na₂SO₄.After filtration and concentration, the crude product was purified bycolumn chromatography to give the title compound (3.8 g, 92%).

(e) Synthesis of the HCl salt of tert-butylspiro[pyrrolidine-3,4′-thieno[3,2-c]chromene]-1-carboxylate

The title compound was synthesized according to General Procedure N.

20. General Procedure T

(a) Synthesis of thiophen-3-ylmethanol

To a solution of thiophene-3-carbaldehyde (10 g, 89.3 mmol) in THF (200mL) at 0° C. was added NaBH₄ (1.7 g, 45.0 mmol) in portions. Afterstirring at 0° C. for 3 h, The reaction was quenched with water andextracted with EtOAc. The combined organic layer was washed with brine,and dried over anhydrous Na₂SO₄. After filtration and concentration, thecrude product was purified by column chromatography to give the titlecompound (9.7 g, 95%).

(b) Synthesis of (2-bromothiophen-3-yl)methanol

The title compound was synthesized according to General Procedure S.

(c) Synthesis of 2-bromothiophene-3-carbaldehyde

To a solution of (2-bromothiophen-3-yl)methanol (5 g, 26.3 mmol) in THF(60 mL) at 0° C. was added Dess-Martin periodinane (13.4 g, 31.6 mmol)in portions. After stirring at 0° C. for 3 h, water and Na₂SO₃ wereadded. The mixture was extracted with DCM, and the combined organiclayers were washed with brine and dried over anhydrous Na₂SO₄. Afterfiltration and concentration, the crude product was purified by columnchromatography to give the title compound (4.1 g, 83%).

(d) Synthesis of 1-(2-bromothiophen-3-yl)-2-nitroethanol

The title compound was synthesized according to General Procedure Q.

(e) Synthesis of (E)-2-bromo-3-(2-nitrovinyl)thiophene

To a solution of 1-(2-bromothiophen-3-yl)-2-nitroethanol (3 g, 12.0mmol), DMAP (146 mg, 1.2 mmol) and Et₃N (2.4 g, 24.0 mmol) in DCM (30mL) was added MsCl (2.4 g, 24.0 mmol) dropwise. The resulting mixturewas then refluxed for 3 h. After cooling, the reaction mixture wasdiluted with water and extracted with DCM. The combined organic layerswere washed with brine and dried over anhydrous Na₂SO₄. After filtrationand concentration, the crude product was purified by columnchromatography to give the title compound (2.5 g, 88%).

(f) Synthesis of 4-(nitromethyl)-4H-thieno[3,2-c]chromene

The title compound was synthesized according to General Procedure S(c).

(g) Synthesis of (4H-thieno[3,2-c]chromen-4-yl)methanamine

To a solution of 4-(nitromethyl)-4H-thieno[3,2-c]chromene (2.5 g, 10.7mmol) in AcOH (20 mL) was added NH₄Cl (5.4 g, 100 mmol) and Fe (2.8 g,50 mmol). After stirring overnight, the reaction mixture was filtered.The filtrate was concentrated under reduced pressure and the residue waspurified by column chromatography to give the title compound (2.2 g,96%).

(h) Synthesis of ethyl (4H-thieno[3,2-c]chromen-4-yl)methylcarbamate

The title compound was synthesized according to General Procedure O.

(i) Synthesis of N-methyl-1-(4H-thieno[3,2-c]chromen-4-yl)methanamine

The title compound was synthesized according to General Procedure O.

(j) Synthesis of the HCl salt ofN-methyl-1-(4H-thieno[3,2-c]chromen-4-yl)methanamine

The title compound was synthesized according to General Procedure N.

21. General Procedure U

(a) Synthesis of 2-(thiophen-3-yl)phenol

The title compound was synthesized according to General Procedure S(c).

(b) Synthesis of (4H-thieno[2,3-c]chromen-4-yl)methanamine

The title compound was synthesized according to General Procedure A.

(c) Synthesis of N-methyl-1-(4H-thieno[2,3-c]chromen-4-yl)methanamine

The title compound was synthesized according to General Procedure O.

(d) Synthesis of the HCl salt ofN-methyl-1-(4H-thieno[2,3-c]chromen-4-yl)methanamine

The title compound was synthesized according to General Procedure N.

22. General Procedure V

(a) Synthesis of (2-(5-bromothiophen-2-yl)ethoxy)triisopropylsilane

The title compound was synthesized according to General Procedure S.

(b) Synthesis of(2-(5-bromo-4-iodothiophen-2-yl)ethoxy)triisopropylsilane

To a solution of (2-(5-bromothiophen-2-yl)ethoxy)triisopropylsilane(7.24 g, 20 mmol) in dry THF (80 mL) at −5° C. was added LDA (20 mL inTHF, 30 mmol) dropwise. After stirred for 1 h, NIS (6.75 g, 30 mmol) indry THF (20 mL) was added dropwise and the resulting mixture was stirredfor another 2 h. The reaction was quenched with water (30 mL) and theresulting mixture was extracted with EtOAc (3×150 mL), washed withbrine, dried over anhydrous Na₂SO₄. After filtration and concentration,the crude product was purified by column chromatography to give thetitle compound (5.9 g, 61%).

(c) Synthesis of(2-(5-bromo-4-(trifluoromethyl)thiophen-2-yl)ethoxy)triisopropylsilane

A solution of CuBr (20 mg, 0.15 mmol) and Me₂S (10 mg, 0.15 mmol) in DMF(10 mL) was stirred at 80° C. for 0.5 h.(2-(5-bromo-4-iodothiophen-2-yl)ethoxy)triisopropylsilane (0.35 g, 0.71mmol) and methyl 3,3-difluoro-3-(fluorosulfonyl)propanoate (0.27 g, 1.42mmol) were added to the reaction mixture. The reaction mixture washeated to 160° C. for 4 h. After that, the mixture was cooled andextracted with hexanes (3×20 mL). The combined organic layers werewashed with brine and dried over anhydrous Na₂SO₄. After filtration andconcentration, the crude product was purified by column chromatographyto give the title compound.

(d) Synthesis of1-(2-bromo-3-(trifluoromethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-N-methylmethanamine

The title compound was synthesized according to General Procedure P.

(e) Synthesis ofN-methyl-1-(3-(trifluoromethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

To a solution of1-(2-bromo-3-(trifluoromethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-N-methylmethanamine(5 mmol) in MeOH (5 mL) was added a catalytic amount of Pd/C. A vacuumwas applied and the reaction vessel was back filled with hydrogen gasthree times. The resulting mixture was stirred under atmospheric H₂.After the reduction was completed, the reaction mixture was filtered andthe filter cake was washed with methanol. The combined filtrate wasconcentrated and purified by column chromatography to give the desiredproduct.

(f) Synthesis of the HCl salt ofN-methyl-1-(3-(trifluoromethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

The title compound was synthesized according to General Procedure N.

23. General Procedure W

(a) Synthesis of 2-bromocyclohexane-1,3-dione

Cyclohexane-1,3-dione (11.2 g, 0.1 mol) was suspended in ice water (70mL) and bromine (5.16 mL, 0.1 mol) was added dropwise over 5 minutes.The resulting suspension was stirred at room temperature for 3 hours.The suspension was filtered and the solid was stirred in water (200 mL)for 30 minutes. The solid was collected by vacuum filtration, rinsedwith water, and dried to render crude product. The crude product wasrecrystallized from ethanol to produce the title compound.

(b) Synthesis of 2-methyl-5,6-dihydrobenzo[d]thiazol-7(4H)-one

To a solution of ethanethioamide (0.75 g, 10 mmol) in ethanol (20 mL) atroom temperature was added 2-bromocyclohexane-1,3-dione (1.9 g, 10 mmol)in portions. The reaction solution was refluxed for 2 hours whilestirring. After removal of solvents, the residue was diluted with waterand washed with diethyl ether. The separated aqueous layer was basifiedwith sodium carbonate solution. The resulting solid was collected byvacuum filtration, rinsed with water. The solid was suspended inmethanol and followed by evaporation to dryness to produce the titlecompound.

(c) Synthesis of2-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-7-carbonitrile

To a stirred and cooled solution of5,6-dihydro-2-methylbenzo[d]thiazol-7(4H)-one (1.67 g, 10 mmol) andTOSMIC (2.5 g, 13 mmol) in a mixture of DME (25 mL) and absolute ethanol(25 mL) was added solid t-BuOK (2.8 g, 24 mmol) portionwise whilekeeping the reaction temperature between 5 and 10° C. The resultingmixture was stirred at room temperature for 30 minutes and at 30-45° C.for 30 minutes. The resulting suspension was cooled to room temperature.The precipitate (TosK) was removed by filtration and rinsed with DME.The combined DME solutions were concentrated under reduced pressure togive the crude product, which was purified by column chromatography.

(d) Synthesis of(2-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)methanamine

The title compound was synthesized according to General Procedure O(h).

(e) Synthesis ofN-methyl-1-(2-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)methanamine

The title compound was synthesized according to General Procedure O.

(f) Synthesis of the HCl salt ofN-methyl-1-(2-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)methanamine

The title compound was synthesized according to General Procedure N.

24. General Procedure X

(a) Synthesis of ethyl 3-bromo-2-oxocyclohexanecarboxylate

The title compound was synthesized according to General Procedure W.

(b) Synthesis of ethyl2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-4-carboxylate

The title compound was synthesized according to General Procedure W.

(c) Synthesis of(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methanol

The title compound was synthesized according to General Procedure O(h).

(d) Synthesis of (2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methylmethanesulfonate

To a solution of(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methanol (3.3 mmol) andEt₃N (1.4 mL, 10 mmol) in THF (10 mL) was added MsCl (0.3 mL, 3.6 mmol)dropwise at room temperature. The resulting mixture was stirred at roomtemperature for 1 hr. The reaction mixture was diluted with water (200mL), filtered, and dried to give the crude product, which was useddirectly in the next step without further purification.

(e) Synthesis of4-(aminomethyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

To a solution of (2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methylmethanesulfonate (3.3 mmol) in DMF (10 mL) was added NaN₃ (0.21 g, 3.3mmol). The resulting mixture was stirred at 85° C. for 30 minutes. Themixture was poured into water (100 mL) and extracted with EtOAc. Theorganic extract was dried over anhydrous sodium sulfate. Afterfiltration and concentration, the crude product was dissolved in THF (20mL) and H₂O (10 mL), Na₂CO₃ (0.35 g, 3.3 mmol) and PPh₃ (0.8 g, 3 mmol)was added. After stirring overnight, the reaction mixture was dilutedwith water (100 mL) and then filtered. The filtrate was extracted withEtOAc, and the organic layer was washed with brine and dried overanhydrous sodium sulfate. After filtration and concentration, the crudeproduct was obtained and used directly in the next step without furtherpurification.

(f) Synthesis ofN-methyl-4-((methylamino)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

The title compound was synthesized according to General Procedure O.

(g) Synthesis of the HCl salt ofN-methyl-4-((methylamino)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

The title compound was synthesized according to General Procedure N.

25. General Procedure Y

(a) Synthesis of 4-methylthiophene-2-carbaldehyde

To a solution of 3-methylthiophene (1.89 g, 15.0 mmol) in dry THF (10mL) at −65° C. was added n-BuLi (15.0 mmol) dropwise. After stirring for30 min, DMF (3.0 g, 10.0 mmol) in dry THF (3 mL) was added dropwise andthe reaction mixture was stirred at −65° C. for 2 h. The reaction waswarmed to room temperature and water was added. The resulting mixturewas extracted with EtOAc (3×100 mL). The combined extract was washedwith brine and dried over anhydrous Na₂SO₄. After filtration andconcentration, the crude product was purified by column chromatographyto give the title compound (7.1 g, 90%).

(b) Synthesis of (E)-ethyl 3-(4-methylthiophen-2-yl)acrylate

The title compound was synthesized according to General Procedure Q.

(c) Synthesis of ethyl 3-(4-methylthiophen-2-yl)-4-nitrobutanoate

The title compound was synthesized according to General Procedure Q.

(d) Synthesis of 3-(4-methylthiophen-2-yl)-4-nitrobutanoic acid

The title compound was synthesized according to General Procedure Q.

(e) Synthesis of3-methyl-6-(nitromethyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-4-one

The title compound was synthesized according to General Procedure Q.

(f) Synthesis of3-methyl-6-(nitromethyl)-5,6-dihydro-4H-cyclopenta[b]thiophene

A solution of3-methyl-6-(nitromethyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-4-one (9.5g) in BH₃.THF (400 mL) was stirred at room temperature overnight. TLCanalysis indicated the consumption of starting material. The reactionmixture was acidified to pH 2 with 10% HCl and stirred for 2 h. Themixture was extracted with EtOAc (100 mL×3). The combined organic phasewas dried with Na₂SO₄, and concentrated in vacuo. The crude product waspurified by flash column chromatography to afford 5 g of title compound(yield: 56.4%).

(g) Synthesis of(3-methyl-5,6-dihydro-4H-cyclopenta[b]thiophen-6-yl)methanamine

To a solution of3-methyl-6-(nitromethyl)-5,6-dihydro-4H-cyclopenta[b]thiophene (5 g) inMeOH (100 mL) was added 10% Pd/C and the reaction was placed under ahydrogen atmosphere using a balloon. The mixture was stirred at roomtemperature overnight. TLC analysis indicated the consumption ofstarting material and the reaction mixture was filtered through a pad ofCelite. The filtrate was concentrated in vacuo. The residue was resolvedin Et₂O, and treated with gaseous HCl at 0° C. for 10 minutes. Theprecipitated product was collected by vacuum filtration and dried togive 4.0 g of HCl salt of the title compound.

(h) SynthesisN-methyl-1-(3-methyl-5,6-dihydro-4H-cyclopenta[b]thiophen-6-yl)methanamine

The title compound was synthesized according to General Procedure O.

(i) Synthesis of the HCl salt ofN-methyl-1-(3-methyl-5,6-dihydro-4H-cyclopenta[b]thiophen-6-yl)methanamine

The title compound was synthesized according to General Procedure N(e).

26. General Procedure Z

(a) Synthesis of 2-bromo-3-methylthiophene

The title compound was synthesized according to General Procedure S.

(b) Synthesis of 5-bromo-4-methylthiophene-2-carbaldehyde

To a solution of 2-bromo-3-methylthiophene (2.66 g, 15.0 mmol) in dryTHF (10 mL) at −65° C. was added LDA solution (15.0 mmol) dropwise.After stirring for 30 min, DMF (3.0 g, 10.0 mmol) in dry THF (3 mL) wasadded dropwise and the reaction was stirred at −65° C. for 2 h. Thereaction was warmed to room temperature and water was added. Thequenched mixture was extracted with EtOAc (3×100 mL). The combinedextract was washed with brine and dried over anhydrous Na₂SO₄. Afterfiltration and concentration, the crude product was purified by columnchromatography to give the title compound.

(c) Synthesis of 4-methylthiophene-2-carbaldehyde

The title compound was synthesized according to General Procedure V(e).

(d) Synthesis of (Z)-ethyl 4-(4-methylthiophen-2-yl)but-3-enoate

The title compound was synthesized according to General Procedure Q.

(e) Synthesis of ethyl 4-(4-methylthiophen-2-yl)butanoate

The title compound was synthesized according to General Procedure V(e).

(f) Synthesis of 4-(4-methylthiophen-2-yl)butanoic acid

The title compound was synthesized according to General Procedure Q.

(g) Synthesis of 3-methyl-6,7-dihydrobenzo[b]thiophen-4(5H)-one

The title compound was synthesized according to General Procedure Q.

(h) Synthesis of3-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carbonitrile

The title compound was synthesized according to General Procedure W.

(i) Synthesis of(3-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-yl)methanamine

The title compound was synthesized according to General Procedure W.

(j) Synthesis ofN-methyl-1-(3-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-yl)methanamine

The title compound was synthesized according to General Procedure O.

(k) Synthesis of the HCl salt of N-methyl-1-(3 methyl 4,5,6,7tetrahydrobenzo[b]thiophen-4-yl)methanamine

The title compound was synthesized according to General Procedure N.

27. General Procedure AA

The above compounds, 4-(thiophen-3-yl)butanoic acid,5,6-dihydrobenzo[b]thiophen-7(4H)-one,4,5,6,7-tetrahydrobenzo[b]thiophene-7-carbonitrile,(4,5,6,7-tetrahydrobenzo[b]thiophen-7-yl)methanamine, andN-methyl-1-(4,5,6,7-tetrahydrobenzo[b]thiophen-7-yl)methanamine, weresynthesized according to General Procedure Z. The HCl salt ofN-methyl-1-(4,5,6,7-tetrahydrobenzo[b]thiophen-7-yl)methanamine wassynthesized according to General Procedure N.

28. General Procedure BB

(a) Synthesis of 6,7-dihydrobenzo[b]thiophen-4(5H)-one

The title compound was synthesized according to General Procedures Q andZ.

(b) Synthesis of 4,5,6,7-tetrahydrobenzo[b]thiophene

A mixture of the starting material (4.93 mmol), ethylene glycol (3.6mL), 88% KOH (0.55 g, 9.8 mol), and 85% hydrazine hydrate (0.62 mL) wasrefluxed for about half an hour. The condenser was then removed to allowthe aqueous liquor to evaporate. The temperature of the reaction mixturereached about 200° C. After the reaction mixture refluxed overnight, itwas cooled, diluted with water and extracted with ether. The combinedether solution was concentrated under reduced pressure to give the crudeproduct, which was purified by column chromatography.

(c) Synthesis of 3-bromo-4,5,6,7-tetrahydrobenzo[b]thiophene

The title compound was synthesized according to General Procedure T.

(d) Synthesis of 2-(4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)ethanol

The title compound was synthesized according to General Procedure P.

(e) Synthesis of4,5,6,7-tetrahydrobenzo[b]thiophene[2,3-c]pyran-7-yl)amine

The title compound was synthesized according to General Procedure B.

(f) Synthesis of4,5,6,7-tetrahydrobenzo[b]thiophene[2,3-c]pyran-7-yl)methanamine

The title compound was synthesized according to General Procedure O(g,h).

(g) Synthesis of4,5,6,7-tetrahydrobenzo[b]thiophene[2,3-c]pyran-7-yl)methanamine

The title compound was synthesized according to General Procedure N(e).

29. General Procedure CC

(a) Synthesis of (S)-(9H-fluoren-9-yl)methyl2-(hydroxymethyl)pyrrolidine-1-carboxylate

The title compound was synthesized according to General Procedure Ousing pyrrolidin-2-ylmethanol as starting material.

(b) Synthesis of (S)-(9H-fluoren-9-yl)methyl2-formylpyrrolidine-1-carboxylate

The title compound was synthesized according to General Procedure O.

(c) Synthesis of (S)-(9H-fluoren-9-yl)methyl2-((R)-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)pyrrolidine-1-carboxylate

The title compound was synthesized according to General Procedure B.Diasteromeric products were separated at this stage by RP-HPLC.

(d) Synthesis of(S)-2-((R)-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)pyrrolidine

The title compound was synthesized according to General Procedure N(d).

(e) Synthesis of the HCl salt of(S)-24(R)-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)pyrrolidine

The title compound was synthesized according to General Procedure N(d).

30. General Procedure DD

(a) (9H-fluoren-9-yl)methyl(R)-1-((S)-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)ethylcarbamate

The title compound was synthesized according to General Procedure O.

(b) (R)-1-((S)-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)ethanamine

The title compound was synthesized according to General Procedure O.

(c) Synthesis of(R)-1-((S)-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)-N-methylethanamine

The title compound was synthesized according to General Procedure O.

(d) Synthesis of the HCl salt of(R)-1-((S)-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)-N-methylethanamine

The title compound was synthesized according to General Procedure O.

31. General Procedure EE

(a) Synthesis of N,N,2-trimethyl-1H-imidazole-1-sulfonamide

The title compound was synthesized according to J. Org. Chem. 1989, 54,1256.

(b) Synthesis of 5-formyl-N,N,2-trimethyl-1H-imidazole-1-sulfonamide

The title compound was synthesized according to General Procedure Y.

(c) Synthesis of5-(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-N,N,2-trimethyl-1H-imidazole-1-sulfonamideand5-(5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)-N,N,2-trimethyl-1H-imidazole-1-sulfonamide

The title compound was synthesized according to General Procedure A andB.

(d) Synthesis of HCl salt of5-(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-N,N,2-trimethyl-1H-imidazole-1-sulfonamideand5-(5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)-N,N,2-trimethyl-1H-imidazole-1-sulfonamide

The title compound was synthesized according to General Procedure J(e).

32. General Procedure FF

(a) Synthesis of (4-chlorophenyl)(2,2-dimethoxyethyl)sulfane

To a solution of 4-chlorobenzenethiol (13 mmol) and Et₃N (1.4 g, 13mmol) in THF (25 mL) at room temperature was added2-bromo-1,1-dimethoxyethane (2.36 g, 13 mmol) in THF (5 mL). Afterstirring at room temperature for 30 minutes, the reaction mixture waspoured into water (200 mL) and extracted with diethyl ether (3×150 mL).The combined organic layer was dried over Na₂SO₄. After filtration andconcentration, the crude product was purified by column chromatographyto give the title compound.

(b) Synthesis of 5-chlorobenzo[b]thiophene

The title compound was synthesized in the presence of PPA according toGeneral Procedure Q(e).

(c) Synthesis of 2-bromo-5-chlorobenzo[b]thiophene

The title compound was synthesized according to General Procedure S.

(d) Synthesis of 2-(5-chlorobenzo[b]thiophen-2-yl)ethanol

The title compound was synthesized according to General Procedure A(a).

(e) Synthesis of2-(5-chlorobenzo[b]thiophen[3,2-c]pyran-4-yl)methanamine

The title compound was synthesized according to General Procedure A(b).

(f) Synthesis of the HCl salt of2-(5-chlorobenzo[b]thiophen[3,2-c]pyran-4-yl)methanamine

The title compound was synthesized according to General Procedure N.

33. General Procedure GG

(a) Synthesis of 3-phenylthiophene

The title compound was synthesized according to General Procedure U.

(b) Synthesis of 2,5-dibromo-3-phenylthiophene

The title compound was synthesized according to General Procedure S.

(c) Synthesis of 2,5-dibromo-3-ethyl-4-phenylthiophene

To a solution of 2,5-dibromo-3-phenylthiophene (2.54 g, 8.0 mmol) in dryTHF (30 mL) at −65° C. was added LDA (8.8 mmol) dropwise. After stirringfor 30 min at −65° C., oxirane (20.0 mmol) was added and the reactionwas stirred for 2 h. The reaction mixture was then warmed to roomtemperature and water was added. The resulting mixture was extractedwith EtOAc (3×100 mL), washed with brine, and dried over anhydrousNa₂SO₄. After filtration and concentration, the crude product waspurified by column chromatography to give the title compound.

(d) Synthesis of 2-(4-phenylthiophen-3-yl)ethanol

The title compound was synthesized according to General Procedure V.

(e) Synthesis ofN-methyl-1-(3-phenyl-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)methanamine

The title compound was synthesized according to General Procedure B.

(f) Synthesis of the HCl salt ofN-methyl-1-(3-phenyl-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)methanamine

The title compound was synthesized according to General Procedure N.

34. General Procedure HH

(a) Synthesis of tert-butyl(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)methyl(methyl)carbamate

The title compound was Boc-protected from the appropriate secondaryamine according to General Procedure M.

(b) Synthesis of tert-butyl(2-bromo-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)methyl(methyl)carbamate

The title compound was synthesized according to General Procedure V.

(c) Synthesis of tert-butyl(2-bromo-3-chloro-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)methyl(methyl)carbamate

The title compound was synthesized according to General Procedure V.

(d) Synthesis of1-(2-bromo-3-chloro-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-N-methylmethanamine

The title compound was synthesized according to General Procedure J.

(e) Synthesis of1-(3-chloro-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-N-methylmethanamine

The title compound was synthesized according to General Procedure V.

(f) Synthesis of the HCl salt of1-(3-chloro-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-N-methylmethanamine

The title compound was synthesized according to General Procedure N.

35. General Procedure II

(a) Synthesis of 5-phenylbenzo[b]thiophene

The title compound was synthesized according to General Procedure S(c).

(b) Synthesis of ethyl 4-oxo-4-(5-phenylbenzo[b]thiophen-3-yl)butanoate

To a solution of 5-phenylbenzo[b]thiophene (1.05 g, 5.0 mmol, 1 eq) inDCM (100 mL) at 0° C. was added ethyl 4-chloro-4-oxobutanoate (0.9 g,21.4 mmol). The resulting mixture was stirred at 0° C. for 30 minutes.SnCl₄ (2.3 mL, 6.0 mmol, 1.2 eq) was added and the mixture was stirredat room temperature overnight. The reaction mixture was quenched withaqueous HCl solution (50 mL, 3 M) and extracted with diethyl ether. Thecombined organic layers were dried over Na₂SO₄. After filtration andconcentration, the crude product was purified by column chromatographyto give the title compound.

(c) Synthesis of 4-oxo-4-(5-phenylbenzo[b]thiophen-3-yl)butanoic acid

The title compound was synthesized according to General Procedure Q.

(d) Synthesis of 4-(5-phenylbenzo[b]thiophen-3-yl)butanoic acid

The title compound was synthesized according to General Procedure BB.

(e) Synthesis of 8-phenyl-2,3-dihydrodibenzo[b,d]thiophen-4(1H)-one

The title compound was synthesized according to General Procedure BB.

(f) Synthesis of 8-phenyl-1,2,3,4-tetrahydrodibenzo[b,d]thiophen-4-amine

To a solution of 8-phenyl-2,3-dihydrodibenzo[b,d]thiophen-4(1H)-one(0.28 g, 1.0 mmol, 1 eq), ammonium acetate (0.77 g, 10 eq) in MeOH (20mL) was added NaBH₃CN (160 mg, 2.5 eq) in one portion. The reactionmixture was heated to 50° C. and stirred for 20 h, After that thesolvent was removed, diluted with saturated NaHCO₃ and extracted withethyl acetate (3×50 mL). The combined organic layers were dried overNa₂SO₄. After filtration and concentration, the residue was purified bysilica gel chromatography to give the title compound (64 mg, 23%).

(g) Synthesis ofN-methyl-8-phenyl-1,2,3,4-tetrahydrodibenzo[b,d]thiophen-4-amine

The title compound was synthesized according to General Procedure O.

(h) Synthesis of HCl salt ofN-methyl-8-phenyl-1,2,3,4-tetrahydrodibenzo[b,d]thiophen-4-amine

The title compound was synthesized according to General Procedure N.

36. General Procedure JJ

(a) Synthesis of1-(2-bromo-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine

The title compound was synthesized according to General Procedure S.

(b) Synthesis of tert-butyl(2-bromo-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)methyl(methyl)carbamate

The title compound was Boc-protected according to General Procedure M.

(c) Synthesis of tert-butyl(2-bromo-3-chloro-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)methyl(methyl)carbamate

The title compound was synthesized according to General Procedure HH.

(d) Synthesis of1-(2-bromo-3-chloro-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine

The title compound was synthesized according to General Procedure J(e).

(e) Synthesis of1-(3-chloro-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine

The title compound was synthesized according to General Procedure V(e).

(f) Synthesis of HCl salt of1-(3-chloro-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine

The title compound was synthesized according to General Procedure N.

37. General Procedure KK

(a) Synthesis of ethyl 2-(2,5-dimethylthiophen-3-yl)-2-oxoacetate

To a solution of AlCl₃ (29.5 g, 221 mmol) in CH₂Cl₂ (150 mL) was added2,5-dimethyl thiophene (6.2 g, 55 mmol) followed by ethyl2-chloro-2-oxoacetate (15.1 g, 110 mmol). The resulting mixture wasstirred at room temperature for 12 h at which time the reaction mixturewas filtered, diluted carefully with H₂O and extracted with EtOAc.Removal of volatiles afforded mostly pure crude material, which was usedin the next step without further purification.

(b) Synthesis of 2-(2,5-dimethylthiophen-3-yl)ethanol

Ethyl 2-(2,5-dimethylthiophen-3-yl)-2-oxoacetate was reduced at ambienttemperature using excess BH₃-DMS in THF over 18 h. Standard work-upprotocols and purification by column chromatography on silica affordedthe desired alcohol product.

(c) Synthesis of(1,3-dimethyl-6,7-dihydro-4H-thieno[3,4-c]pyran-4-yl)methanamine

The title compound was synthesized according to General Procedure D.

B. General Procedure CS (Chiral Separation)

Normal phase chiral separation of the racemic compounds disclosed hereinwas carried out using Chiral Technologies AS, AD, OJ and OD columns andthe specified solvent system.

The following abbreviations were used:

IHD 5=5% isopropanol/95% hexanes/0.1% diethylamine;

IHD 10=10% isopropanol/90% hexanes/0.1% diethyl amine;

MEHD 5=2.5% Methanol/2.5% ethanol/95% hexanes/0.1% diethylamine; and

MEHD 2.5=1.25% ethanol/1.25% methanol/97.5% hexanes/0.1% diethylamine.

The Faster Moving Enantiomer (FME) was the earlier eluting enantiomerand the Slower Moving Enantiomer (SME) was the later eluting enantiomer.When the free primary or secondary amines disclosed herein were notseparable by column chromatography, they were N-BOC or N-TROC protectedusing standard methods and then separated by column chromatography,which typically improved the separation. Following separation of theprotected amines, the protecting groups were removed using standardmethods (e.g., HCl for BOC, Zn dust/NH₄Cl for TROC).

SFC (supercritical CO₂ fluid chromatography) chiral separation was doneusing the specified column and co-solvent and CO₂ total flows werebetween 60 to 80 g/minute.

C. Compounds

The following compounds were prepared using the above generalprocedures.

Salt Compd. or Method of No. Structure FB* Preparation Analytical Data 1

HCl A ¹H NMR (CD₃OD): 7.29 (d, J = 5.0 Hz, 1H), 6.89 (d, J = 5.0 Hz,1H), 4.94 (d, J = 8.0 Hz, 1H), 4.29-4.23 (m, 1H), 3.85-3.78 (m, 1H),3.46 (d, J = 13.0 Hz, 1H), 3.14 (dd, J = 9.5, 11.5 Hz, 1H), 3.05-2.97(m, 1H), 2.80 (d, J = 16.0 Hz, 1H). 2

HCl CS; BOC deriv of compound 1 was FME with OD and IHD 5 ¹H NMR(CD₃OD): 7.29 (d, J = 5.0 Hz, 1H), 6.89 (d, J = 5.0 Hz, 1H), 4.94 (d, J= 8.0 Hz, 1H), 4.29-4.23 (m, 1H), 3.85-3.78 (m, 1H), 3.46 (d, J = 13.0Hz, 1H), 3.14 (dd, J = 9.5, 11.5 Hz, 1H), 3.05-2.97 (m, 1H), 2.80 (d, J= 16.0 IIz, 1H). 3

HCl CS; BOC deriv of compound 1 was SME with OD and IHD 5 ¹H NMR(CD₃OD): 7.29 (d, J = 5.0 Hz, 1H), 6.89 (d, J = 5.0 Hz, 1H), 4.94 (d, J= 8.0 Hz, 1H), 4.29-4.23 (m, 1H), 3.85-3.78 (m, 1H), 3.46 (d, J = 13.0Hz, 1H), 3.14 (dd, J = 9.5, 11.5 Hz, 1H), 3.05-2.97 (m, 1H), 2.80 (d, J= 16.0 IIz, 1II). 4

HCl A LC-MS (6 min method): 0.24 minute, M⁺ 184 @ 0.26 min.; ¹H NMR(CD₃OD): 7.30 (d, J = 5.50 Hz, 1H), 6.90 (d, J = 5.50 Hz, 1H), 5.00 (dd,J = 2.57, 8.80 Hz, 1H), 4.30-4.26 (m, 1H), 3.89-3.80 (m, 1H), 3.57-3.53(m, 1H), 3.28-3.21 (m, 1H), 3.05-3.01 (m, 1H), 2.84- 2.79 (m, 1H), 2.74(s, 3H). 5

HCl A ¹H NMR (CD₃OD): δ 6.54 (s, 1H), 4.91-4.85 (m, 1H), 4.26-4.21 (m,1H), 3.80 (td, J = 3.5, 10.0 Hz, 1H), 3.47 (dd, J = 3.0, 13.0 Hz, 1H),3.20 (dd, J = 8.5, 13.0 Hz, 1H), 2.93-2.88 (m, 1H), 2.72 (s, 3H),2.71-2.66 (m, 1H), 2.42 (s, 3H). 6

HCl A ¹H NMR (CD₃OD): δ 7.22 (d, J = 5.10 Hz, 1H), 6.87 (d, J = 5.10 Hz,1H), 3.97 (t, J = 5.50 Hz, 2H), 3.40- 3.25 (m, 4H), 2.84 (t, J = 5.5 Hz,2H), 2.22-2.14 (m, 2H), 2.06-2.02 (m, 2H). 7

HCl A LC-MS (3.0 min method): 0.98 minute, M⁺ 220; ¹H-NMR (400 MHz,CD₃OD) δ 7.86 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.40 (td, J= 7.2, 0.8 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 5.27 (dd, J = 8.4, 2.0 Hz,1H), 4.25 (m, 1H), 3.94 (m, 1H), 3.62 (dd, J = 13.2, 2.0 Hz, 1H), 3.35(m, 1H), 3.00 (m, 2H). 8

HCl A LC-MS (3.0 min method): 1.00 minute, M⁺ 234; ¹H-NMR (400 MHz,CD₃OD) δ 7.85 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.40 (t, J= 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 5.34 (d, J = 8.8 Hz, 1H), 4.26(m, 1H), 3.94 (m, 1H), 3.68 (dd, J = 13.2, 2.0 Hz, 1H), 3.42 (m, 1H),2.98 (m, 2H), 2.77 (s, 3H). 9

HCl A ¹H NMR (DMSO-d): δ 8.22 (br s, 3H), 6.70 (s, 1H), 4.85-4.83 (d, J= 8.01 Hz, 1H), 4.13-4.07 (m, 1H), 3.78-3.70 (m, 1H), 3.29 (s, 1H),2.91-2.67 (m, 5H), 1.22-1.18 (t, J = 7.50 Hz, 3H). 10

HCl A ¹H NMR (DMSO-d⁶): δ 9.07 (br s, 1H), 8.67 (br s, 1H), 6.60 (s,1H), 4.94-4.92 (d, J = 8.0 Hz, 1H), 4.15-4.08 (m, 1H), 3.80-3.72 (m,1H), 3.46-3.42 (d, J = 12.3 Hz, 1H), 3.13-3.09 (m, 1H), 2.87-2.68 (m,4H), 2.57 (s, 3H), 1.24-1.19 (t, J = 7.5 Hz, 3H). 11

HCl A ¹H NMR (DMSO-d⁶ + D₂O): δ 7.02 (s, 1H), 4.81-4.78 (dd, J₁ = 2.1Hz, J₂ = 6.5 Hz, 1H), 4.15-4.08 (m, 1H), 3.80-3.72 (m, 1H), 3.35-3.29(dd, J₁= 2.9 Hz, J₂ = 13.3 Hz, 1H), 3.02- 2.95 (m, 1H), 2.81-2.72 (m,2H). 12

HCl A ¹H NMR (DMSO-d⁶): δ 9.26 (br s, 1H), 8.80 (br s, 1H), 7.04 (s,1H), 4.98-4.94 (dd, J₁ = 1.8 Hz, J ₂ = 9.2 Hz, 1H), 4.16-4.09 (m, 1H),3.82- 3.74 (m, 1H), 3.47-3.36 (d, J = 29.1 Hz, 1H), 3.13 (m, 1H),2.87-2.69 (m, 2H), 2.56 (s, 3H). 13

HCl F GC-MS m/z 139 (M⁺); ¹H NMR (DMSO-d⁶): δ 9.02 (s, 1H), 8.65 (s,1H), 7.41-7.40 (d, J = 5.19 Hz, 1H), 6.99-6.97 (d, J = 5.19 Hz, 1H),5.03-5.00 (d, J = 8.13 Hz, 1H), 4.21-4.12 (m, 1H), 3.83-3.75 (m, 1H),3.52-3.48 (d, J = 12.43 Hz, 1H), 3.13-2.72 (m, 5H), 1.25-1.20 (t, J =7.26 Hz, 3H). 14

FB F GC-MS m/z 211 (M⁺); ¹H NMR (CDCl₃): δ 7.12-7.11 (d, J = 5.13 Hz,1H), 6.79-6.78 (d, J = 5.13 Hz, 1H), 4.85-4.82 (dd, J₁ = 2.04 Hz, J₂ =8.82 Hz, 1H), 4.26-4.20 (m, 1H), 3.84-3.75 (m, 1H), 3.06-2.95 (m, 2II),2.90-2.83 (m, 1II), 2.79-2.72 (m, 1H), 2.69-2.58 (m, 2H), 1.61- 1.50 (m,2H), 0.97-0.92 (t, J = 14.80 Hz, 3H). 15

FB F ¹H NMR (CDCl₃): δ 7.12-7.10 (d, J = 5.16 Hz, 1H), 6.79-6.78 (d, J =5.16 Hz, 1H), 4.82-4.79 (dd, J₁ = 2.34 Hz, J₂ = 9.18 Hz, 1H), 4.25- 4.19(m, 1H), 3.83-3.75 (m, 1H), 3.08-2.99 (m, 2H), 2.87-2.73 (m, 3H), 1.11(s, 3H), 1.09 (s, 3H). 16

HCl F GC-MS m/z 209 (M⁺); ¹H NMR (DMSO-d⁶): δ 9.35 (br s, 1H), 9.03 (brs, 9.03, 1H), 7.41-7.40 (d, J = 5.20 Hz, 1H), 7.04-7.02 (d, J = 5.20 Hz,1H), 5.08-5.05 (d, J = 8.49 Hz, 1H), 4.18-4.12 (m, 1H), 3.82-3.74 (m,1H), 3.62-3.58 (d, J = 12.82 Hz, 1H), 3.22-3.14 (t, J = 11.65 Hz, 1H),2.96-2.72 (m, 3H), 0.99-0.82 (m, 2H), 0.79-0.72 (m, 2H). 17

FB F GC-MS m/z 223 (M⁺); ¹H NMR (CDCl₃): δ 7.10-7.08 (d, J = 4.95 Hz,1H), 6.86-6.84 (d, J = 4.95 Hz, 1H), 4.87-4.82 (m, 1H), 4.28-4.22 (m,1H), 3.82-3.74 (m, 1H), 3.04- 2.94 (m, 1H), 2.85-2.70 (m, 3H), 2.67-2.56(m, 4H), 1.89-1.76 (m, 4H). 18

FB F ¹H NMR (CDCl₃): δ 7.10-7.09 (d, J = 5.1 Hz, 1H), 6.91-6.89 (d, J =5.1 Hz, 1H), 4.90-4.84 (m, 1H), 4.27- 4.21 (m, 1H), 3.81-3.73 (m, 1H),3.04-2.94 (m, 1H), 2.78-2.70 (m, 1H), 2.67-2.62 (m, 2H), 2.55-2.52 (m,4H), 1.69-1.59 (m, 4H), 1.50- 1.43 (m, 2H). 19

FB F GC-MS m/z 251 (M⁺); ¹H NMR (DMSO-d⁶): δ 7.28-7.27 (d, J = 5.16 IIz,1II), 7.03-7.02 (d, J = 5.16 IIz, 1H), 4.68-4.64 (t, J = 5.82 Hz, 1H),4.11-4.04 (m, 1H), 3.70-3.61 (m, 1H), 2.83-2.64 (m, 8H), 1.55 (s, 8H).20

HCl A ¹H NMR (CD₃OD): δ 7.26 (d, J = 5.1, Hz, 1H), 6.96 (d, J = 5.1 Hz,1H), 4.01-3.97 (m, 2H), 3.59-3.53 (m, 3H), 3.38 (d, J = 6.8 Hz, 1H),2.89 (brs, 2H), 2.38-2.36 (m, 2H). 21

HCl A ¹H NMR (CD₃OD): δ 7.26 (d, J = 5.0 Hz, 1H), 6.94 (d, J = 5.0 Hz,1H), 4.00 (t, J = 5.1 Hz, 2H), 3.33- 3.21 (m, 3H), 3.08 (apt, J = 2.8Hz, 1H), 2.87 (t, J = 5.1 Hz, 2H), 2.18- 2.11 (m, 1H), 2.04-1.97 (m,2H), 1.84-1.80 (m, 1H). 22

formate A ¹H NMR (CD₃OD): δ 7.29 (d, J = 5.0 Hz, 1H), 6.88 (d, J = 5.0Hz, 1H), 5.14 (apd, J = 6.0 Hz, 1H), 4.27 (m, 1H), 3.85 (dr, J = 11.0,3.0 Hz, 1H), 3.67 (m, 1H), 3.38-3.25 (m, 1H), 3.04-2.77 (m, 2H), 3.00(s, 3H), 2.92 (s, 3H). 23

HCl A ¹H NMR (DMSO-d⁶): δ 8.18 (br s, 3H), 6.69 (s, 1H), 4.84-4.82 (d, J= 7.5 Hz, 1H), 4.14-4.07 (m, 1H), 3.78-3.70 (m, 1H), 3.29 (s, 1H),2.95-2.66 (m, 5H), 1.65-1.53 (m, 2H), 1.04-0.92 (t, J = 7.32 Hz, 3H). 24

HCl A ¹H NMR (DMSO-d⁶): δ 9.11 (br s, 1H), 9.69 (br, s, 1H), 6.65 (s,1H), 4.95-4.92 (d, J = 7.9 Hz, 1H), 4.15- 4.08 (m, 1H), 3.80-3.72 (m,1H), 3.4 (m, 1H), 3.1 (m, 1H), 2.87-2.78 (m, 1H), 2.73-2.67 (m, 3H),2.57 (s, 3H), 1.66-1.53 (m, 2H), 0.94-0.89 (m, 3H). 25

HCl A ¹H NMR (DMSO-d⁶ + D₂O): δ 7.59-7.57 (d, J = 7.5 Hz, 2H), 7.43-7.38 (t, 3H), 7.32-7.27 (t, 1H), 4.90- 4.87 (d, J = 7.1 Hz, 1H),4.19-4.15 (m, 1H), 3.82-3.79 (m, 1H), 3.45- 3.40 (dd, J₁ = 2.8 Hz, J₂ =13.3 Hz, 1H), 3.09-3.02 (m, 1H), 2.92-2.82 (m, 2II). 26

HCl A ¹H NMR (DMSO-d⁶): δ 9.01 (br s, 1H), 8.69 (br, s, 1H), 7.60-7.58(d, J = 7.2 Hz, 2H), 7.45-7.38 (m, 3H), 7.33-7.28 (t, J = 7.20 Hz, 1H),5.03- 5.00 (d, J = 7.7 Hz, 1H), 4.22-4.09 (m, 1H), 3.86-3.78 (m, 1H),3.59- 3.52 (m, 1H), 3.29-3.17 (m, 1H), 2.93-2.79 (m, 2H), 2.53-2.48 (t,J = 5.31 Hz, 3H). 27

IICl CS; FME of SFC separation of BOC protected Compound 4, usingisocratic 10% [(1:1:2 MeOH:EtOH: Hexanes (1% isopropylamine))] LC-MS (6minute method on lab 209 instrument): 0.24 minute, M⁺ 184 @ 0.26 min.;¹H NMR (CD₃OD): δ 7.30 (d, J = 5.50 Hz, 1H), 6.90 (d, J = 5.50 Hz, 1H),5.00 (dd, J = 2.57, 8.80 Hz, 1H), 4.30- 4.26 (m, 1II), 3.89-3.80 (m,1II), 3.57-3.53 (m, 1H), 3.28-3.21 (m, 1H), 3.05-3.01 (m, 1H), 2.84-2.79(m, 1H), 2.74 (s, 3H). in CO₂ on a LUX-2 5 μ in and flow of 60 g/min 28

HCl CS; SME of SFC separation of BOC protected Compound 4, usingisocratic 10% [(1:1:2 MeOH:EtOH: Hexanes (1% isopropylamine))] LC-MS (6min method): 0.24 minute, M⁺ 184 @ 0.26 min.; ¹H NMR (CD₃OD): δ 7.30 (d,J = 5.50 Hz, 1H), 6.90 (d, J = 5.50 Hz, 1H), 5.00 (dd, J = 2.57, 8.80Hz, 1H), 4.30-4.26 (m, 1H), 3.89-3.80 (m, 1H), 3.57-3.53 (m, 1H),3.28-3.21 (m, 1H), 3.05-3.01 (m, 1H), 2.84- 2.79 (m, 1H), 2.74 (s, 3H).in CO₂ on a LUX-2 5 μ in and flow of 60 g/min 29

HCl A ¹H NMR (DMSO-d⁶): δ 8.14 (br s, 3H), 7.00 (s, 1H), 4.97-4.90 (m,1H), 4.02-3.94 (m, 1H), 3.85-3.78 (m, 1H), 3.11-3.08 (t, J = 10.66 Hz,2H), 2.88-2.73 (m, 2H), 2.13-2.12 (d, J = 0.8 Hz, 3H). 30

HCl A ¹H NMR (DMSO-d⁶): δ 8.06 (br s, 3H), 7.02 (s, 1H), 4.97-4.93 (dd,J₁ = 3.5 Hz, J₂ = 9.1 Hz, 1H), 4.03-3.95 (m, 1H), 3.86-3.79 (m, 1H),3.09 (br s, 2H), 2.84-2.73 (m, 2H), 2.47-2.37 (m, 2H), 1.21-1.17 (t, J =7.41 Hz, 3H). 31

HCl A ¹H NMR (DMSO-d⁶): δ 7.96 (br s, 3H), 7.02 (s, 1H), 4.92-4.90 (d, J= 6.75 Hz, 1H), 4.03-3.95 (m, 1H), 3.86-3.79 (m, 1H), 3.09-3.08 (d, J =3.96 Hz, 2H), 2.89-2.78 (m, 2H), 2.43-2.38 (t, J = 6.84 Hz, 2H), 1.70-1.54 (m, 2H), 0.97-0.92 (t, J = 7.31 Hz, 3H). 32

HCl A ¹H NMR (DMSO-d⁶ +D₂O): δ 7.46- 7.35 (m, 5H), 7.30 (s, 1H), 5.27-5.24 (d, J = 8.49 Hz, 1H), 4.05-3.98 (m, 1H), 3.88-3.82 (m, 1H), 2.88(s, 2H), 2.71-2.64 (m, 1H), 2.47-2.46 (d, J = 2.85 Hz, 1H). 33

HCl A GC-MS m/z 197 (M⁺); ¹H NMR (D₂O): δ 4.95-4.91 (t, J = 5.1 Hz, 1H),4.04-3.97 (m, 1H), 3.85-3.78 (m, 1H), 3.30-3.28 (d, J = 5.01 Hz, 2H),2.76-2.72 (t, J = 5.33 Hz, 2H), 2.21 (s, 3H), 1.92 (s, 3H). 34

HCl A LC-MS (6 min method): 0.48 minute, M⁺ 184 @ 0.48 min.; ¹H NMR(CD₃OD): δ 7.28 (d, J = 5.0 Hz, 1H), 6.90 (d, J = 5.0 Hz, 1H), 4.11-4.07(m, 1H), 3.97-3.91 (m, 1H), 3.33-3.00 (m, 1H), 3.16 (d, J = 13.0 Hz,1H), 3.02-2.94 (m, 1H), 2.76 (d, J = 6.1 Hz, 1H), 1.50 (s, 3II). 35

HCl A ¹H NMR (CD₃OD): δ 7.23 (d, J = 5.0 Hz, 1H), 6.84 (d, J = 5.0 Hz,1H), 3.97 (t, J = 5.0 Hz, 2H), 3.39 (brs, 4H), 2.92 (s, 3H), 2.84 (t, J= 5.0 Hz, 2H), 2.17-1.18 (m, 4H). 36

HCl B ¹H NMR (CD₃OD): δ 7.36 (d, J = 4.4 Hz, 1H), 6.91 (d, J = 4.77 Hz.1H), 5.08 (d, J = 7.7 Hz, 1H), 4.27- 4.23 (m, 1H), 3.84-3.78 (m, 1H),3.42-3.38 (m, 1H), 3.17-3.12 (m, 1H), 2.91-2.83 (m, 1H), 2.70-2.65 (m,1H). 37

formate E ¹H NMR (CD₃OD): δ 7.20 (d, J = 5.1 Hz, 1H), 7.08 (d, J = 5.1Hz, 1H), 3.25 (d, J = 13.0 Hz, 1H), 3.07 (d, J = 13.0 Hz, 1H), 2.83-2.79(m, 2H), 2.04-1.88 (m, 4H). 38

HCl L ¹H NMR (CD₃OD): δ 7.44 (s, 1H), 4.96-4.92 (m, 1H), 4.32-4.28 (m,1H), 3.86 (dt, J = 13.0, 3.5 Hz, 1H), 3.51 (d, J = 13.0 Hz, 1H),3.20-3.15 (m, 1H), 3.10-3.04 (m, 1H), 2.90- 2.86 (m, 1H). 39

HCl L ¹H NMR (CD₃OD): δ 7.42 (s, 1H), 5.00-4.98 (m, 1H), 4.32-4.28 (m,1H), 3.84 (t, J = 13.0, 1H), 3.57 (d, J = 13.0 Hz, 1H), 3.30-3.20 (m,1H), 3.09-3.02 (m, 1H), 2.91-2.86 (m, 1H), 2.74 (s, 3H). 40

HCl A ¹H NMR (CD₃OD): δ 7.91 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz,1H), 7.41 (dt, J = 1.0, 7.5 Hz, 1H), 7.33 (dt, J = 1.0 , 7.5 Hz, 1H),4.08 (dt, J = 1.5, 5.5 Hz, 2H), 3.74 (d, J = 13.0 Hz, 1H), 3.42-3.30 (m,3H), 3.00 (dt, J = 1.5, 5.5 Hz, 2H), 2.52- 2.44 (m, 1H), 2.27 (tq, J =4.0, 14.0 Hz, 1H), 2.08 (dd, J = 2.0, 14.0 Hz, 1H), 1.89 (d, J = 14.0Hz, 1H). 41

HCl CS: FME of separation of Compound 7, on AD with IHD 10 ¹H NMR(CD₃OD): δ 7.86 (d, J = 7.5 Hz, 1H) 7.67 (d, J = 7.5 Hz, 1H), 7.40 (dt,J = 1.0, 7.5 Hz, 1H), 7.34 (dt, J = 1.0, 7.5 Hz, 1H), 5.29- 5.25 (m,1H), 4.28-4.22 (m, 1H), 3.96-3.90 (m, 1H), 3.61 (dd, J = 1.5, 13.5 Hz,1H), 3.37-3.30 (m, 1H), 3.09-2.91 (m, 2H). 42

HCl CS: SME of separation of Compound 7, on AD with IHD 10 ¹H NMR(CD₃OD): δ 7.86 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1II), 7.40(dt, J = 1.0, 7.5 IIz, 1II), 7.34 (dt, J = 1.0, 7.5 Hz, 1H), 5.29- 5.25(m, 1H), 4.28-4.22 (m, 1H), 3.96-3.90 (m, 1H), 3.61 (dd, J = 1.5, 13.5Hz, 1H), 3.37-3.30 (m, 1H), 3.09-2.91 (m, 2H). 43

HCl CS; FME of Compound 20 on AD with MEHD 5 ¹H NMR (CD₃OD): δ 7.26 (d,J = 5.1, Hz, 1H), 6.96 (d, J = 5.1 Hz, 1H), 4.01-3.97 (m, 2H), 3.59-3.53(m, 3H), 3.38 (d, J = 6.8 Hz, 1H), 2.89 (brs, 2H), 2.38-2.36 (m, 2H). 44

HCl CS: FME of N- Troc deriv. on OD with IHD 5 ¹H NMR (CD₃OD): δ 6.53(s, 1H), 4.86 (s, 1H), 4.25-4.20 (m, 1H), 3.82-3.76 (m, 1H), 3.39 (dd, J= 2.93, 13.2 Hz, 1H), 3.08 (dd, J = 8.06, 13.2 Hz, 1H), 2.96-2.88 (m,1H), 2.70-2.66 (m, 1H), 2.42 (s, 3H). 45

HCl CS: SME of N- Troc deriv. on OD with IHD 5 ¹H NMR (CD₃OD): δ 6.53(s, 1H), 4.86 (s, 1H), 4.25-4.20 (m, 1H), 3.82-3.76 (m, 1H), 3.39 (dd, J= 2.93, 13.2 Hz, 1H), 3.08 (dd, J = 8.06, 13.2 Hz, 1H), 2.96-2.88 (m,1II), 2.70-2.66 (m, 1II), 2.42 (s, 3H). 46

HCl CS; SME of Compound 20 on AD with MEHD 5 ¹H NMR (CD₃OD): δ 7.26 (d,J = 5.1, Hz, 1H), 6.96 (d, J = 5.1 Hz, 1H), 4.01-3.97 (m, 2H), 3.59-3.53(m, 3H), 3.38 (d, J = 6.8 Hz, 1H), 2.89 (brs, 2H), 2.38-2.36 (m, 2H). 47

HCl J LC-MS m/z 247.2 (MH⁺); ¹H NMR (DMSO-d⁶): δ 8.83-8.81 (d, J = 6.78Hz, 2H), 8.38 (s, 3H), 8.25 (s, 1H), 8.17-8.14 (d, J = 6.78 Hz, 2H),5.02-5.00 (d, J = 7.65 Hz, 1H), 4.23-4.17 (m, 1H), 3.94-3.78 (m, 1H),3.47-3.46 (m, 1H), 3.11-2.90 (m, 3H). 48

HCl J LC-MS m/z 261.3 (MH⁺); ¹H NMR (DMSO-d⁶): δ 9.61 (br s, 1H), 8.00(br s, 1H), 8.84-8.82 (d, J = 6.75 Hz, 1H), 8.23 (s, 1H), 8.16-8.13 (d,J = 6.75 Hz, 1H), 5.16-5.13 (d, J = 8.25 IIz, 1II), 4.30-4.17 (m, 1II),3.88-3.80 (m, 1H), 3.59-3.53 (m, 1H), 3.27-3.16 (m, 1H), 3.08-2.88 (m,2H), 2.61-2.58 (t, J = 5.19 Hz, 3H). 49

HCl J LC-MS m/z 247.2 (MH⁺); ¹H NMR (DMSO-d⁶): δ 9.11 (br s, 1H), 8.98-8.95 (d, J = 4.83 Hz, 1H), 8.51-8.48 (d, J = 8.25 Hz, 1H), 8.35 (br s,3H), 7.94-7.86 (m, 2H), 4.99-4.97 (d, J = 7.74 Hz, 1H), 4.22-4.15 (m,1H), 3.85-3.77 (m, 1H), 3.42-3.39 (m, 1H), 3.08-2.89 (m, 3H). 50

HCl J LC-MS m/z 261.2 (MH⁺); ¹H NMR (DMSO-d⁶): δ 9.37 (br s, 1H), 9.03(s, 1H), 8.85 (s, 1H), 8.67-8.65 (d, J = 5.01 Hz, 1H), 8.38-8.36 (d, J =7.86 Hz, 1H), 7.81-7.77 (m, 2H), 5.10-5.08 (d, J = 7.98 Hz, 1H),4.23-4.16 (m, 1H), 3.87-3.79 (m, 1H), 3.55-3.48 (m, 1H), 3.26-3.17 (m,1H), 3.03-2.85 (m, 2H), 2.61- 2.58 (t, J = 5.31 Hz, 3H). 51

HCl I LC-MS m/z 247.2 (MH⁺); ¹H NMR (DMSO-d⁶): δ 8.87-8.85 (d, J = 6.69Hz, 2H), 8.22 (br s, 3H), 8.09-8.07 (d, J = 6.69 Hz, 2H), 8.05 (s, 1H),5.62-5.60 (d, J = 8.64 Hz, 1H), 4.10-4.02 (m, 1H), 3.93-3.86 (m, 1H),3.00-2.92 (m, 2H), 2.89-2.77 (m, 1H), 2.57-2.51 (m, 1H). 52

HCl I LC-MS m/z 261.3 (MH⁺); ¹H NMR (DMSO-d⁶): δ 9.72 (br s, 1H), 8.88-8.86 (d, J = 6.75 IIz, 2II), 8.69 (br s, 1H), 8.17-8.15 (d, J = 6.75 Hz,2H), 8.11 (s, 1H), 5.77-5.73 (d, J = 9.24 Hz, 1H), 4.14-4.04 (m, 1H),3.94- 3.87 (m, 1H), 3.06-2.94 (m, 3H), 2.66-2.60 (m, 1H), 2.42-2.41 (t,J = 5.28 Hz, 3H). 53

HCl I LC-MS m/z 247.2 (MH⁺); ¹H NMR (DMSO-d⁶): δ 8.97-8.96 (d, J = 1.77Hz, 1H), 8.84-8.83 (d, J = 4.53 Hz, 1H), 8.54-8.51 (d, J = 8.22 Hz, 1H),8.17 (s, 3H), 8.07-7.95 (dd, J₁ = 5.49 Hz, J₂ = 8.01 Hz, 1H), 7.76 (s,1H), 5.50-5.47 (d, J = 8.85 Hz, 1H), 4.07-4.01 (m, 1H), 3.91-3.84 (m,1H), 2.95-2.93 (m, 2H), 2.83-2.74 (m, 1H), 2.45-2.35 (m, 1H). 54

HCl I LC-MS m/z 261.3 (MH⁺); ¹H NMR (DMSO-d⁶): δ 9.26 (br s, 1H), 8.90-8.89 (d, J = 1.92 Hz, 1H), 8.79-8.77 (dd, J₁ = 1.22 Hz, J₂ = 5.27 Hz,1H), 8.59 (br s, 1H), 8.39-8.36 (d, J = 7.62 Hz, 1H), 7.87-7.83 (dd, J₁= 5.43 Hz, J₂ = 7.83 Hz, 1H), 7.71 (s, 1H), 5.59-5.56 (d, J = 9.48 Hz,1H), 4.13-4.08 (m, 1H), 3.94-3.85 (m, 1H), 3.05-2.93 (m, 3H), 2.65-2.60(m, 1H), 2.39-2.35 (t, J = 5.28 Hz, 3H). 55

HCl H LC-MS m/z 253.3 (MH⁺); ¹H NMR (DMSO-d⁶ + D₂O): δ 4.69-4.67 (d, J =7.68 Hz, 1H), 4.09-4.06 (m, 1H), 3.73-3.71 (m, 2H), 3.28-3.22 (dd, J₁ =2.52 Hz, J₂ = 13.30 Hz, 1H), 2.99- 2.90 (m, 4H), 2.78-2.68 (m, 1H), 2.56(s, 1H), 1.56 (s, 5H), 1.47-1.46 (m, 2II). 56

HCl H LC-MS m/z 277.3 (M + Na⁺); ¹H NMR (DMSO-d⁶): δ 8.01 (s, 3H), 6.05(s, 1H), 4.74-4.72 (d, J = 7.44 Hz, 1H), 4.14-4.08 (m, 1H), 3.78- 3.69(m, 5H), 3.35-3.29 (m, 1H), 3.00-2.97 (m, 5H), 2.77-2.70 (m, 1H),2.62-2.56 (m, 1H). 57

HCl CS; FME of SFC separation of Compound 5, using isocratic 25% [(75:25MeOH:iPrOH (2% isopropylamine))] in CO₂ on a ¹H NMR (CD₃OD): δ 6.54 (s,1H), 4.91-4.85 (m, 1H), 4.26-4.21 (m, 1H), 3.80 (td, J = 3.5, 10.0 Hz,1H), 3.47 (dd, J = 3.0, 13.0 Hz, 1H), 3.20 (dd, J = 8.5, 13.0 Hz, 1H),2.93-2.88 (m, 1H), 2.72 (s, 3H), 2.71-2.66 (m, 1H), 2.42 (s, 3H).ChiralPak AD- H and flow of 60 g/min 58

HCl CS; SME of SFC separation of Compound 5, using isocratic 25% [(75:25MeOH:iPrOH (2% isopropylamine))] in CO₂ on a ¹H NMR (CD₃OD): δ 6.54 (s,1H), 4.91-4.85 (m, 1H), 4.26-4.21 (m, 1H), 3.80 (td, J = 3.5, 10.0 Hz,1H), 3.47 (dd, J = 3.0, 13.0 Hz, 1H), 3.20 (dd, J = 8.5, 13.0 Hz, 1H),2.93-2.88 (m, 1II), 2.72 (s, 3II), 2.71-2.66 (m, 1H), 2.42 (s, 3H).ChiralPak AD- H and flow of 60 g/min 59

HCl H LC-MS m/z 200.3 (MH⁺); ¹H NMR (DMSO-d⁶): δ 8.11 (s, 3H), 6.21 (s,1H), 4.76-4.73 (d, J = 7.14 Hz, 1H), 4.15-4.08 (m, 1II), 3.79-3.72 (m,4H), 3.31-3.26 (m, 1H), 2.98-2.89 (m, 1H), 2.78-2.68 (m, 1H), 2.60- 2.54(m, 1H). 60

HCl H LC-MS m/z 214.3 (MH⁺); ¹H NMR (DMSO-d⁶): δ 9.09 (br s, 1H), 8.67(br s, 1H), 6.15 (s, 1H), 4.87-4.85 (d, J = 7.7 Hz, 1H), 4.15-4.08 (m,1H), 3.80-3.73 (m, 4H), 3.34 (s, 1H), 3.15-3.05 (m, 1H), 2.77-2.68 (m,1H), 2.61-2.55 (m, 4H). 61

HCl H LC-MS m/z 213.3 (MH⁺); ¹H NMR (DMSO-d⁶ + D₂O): δ 5.74 (s, 1H),4.71-4.68 (d, J = 7.03 Hz, 1H), 4.12-4.05 (m, 1H), 3.79-3.68 (m, 1H),3.33-3.25 (m, 1H), 2.95-2.88 (m, 1H), 2.78 (s, 6H), 2.71-2.67 (m, 1H),2.59-2.58 (m, 1H). 62

HCl H LC-MS m/z 227.3 (MH⁺); ¹H NMR (DMSO-d⁶): δ 9.11 (br s, 1H), 8.65(br s, 1H), 5.73 (s, 1H), 4.87-4.83 (d, J = 9.54 Hz, 1H), 4.13-4.07 (m,1H), 3.78-3.72 (m, 1H), 3.43-3.39 (m, 1H), 3.16-3.06 (m, 1H), 2.79- 2.71(m, 7H), 2.58-2.55 (m, 4H). 63

HCl A ¹H NMR (CD₃OD): δ 6.59 (s, 1H), 3.97 (t, J = 5.0 Hz, 2H),3.33-3.24 (m, 3H), 3.05 (dt, J = 3.0, 13.0 Hz, 1H), 2.77 (t, J = 5.0 Hz,2H), 2.41 (s, 3H), 2.16-2.08 (m, 1H), 2.00- 1.88 (m, 2H), 1.80 (d, J =14.0 Hz, 1H). 64

HCl A LC-MS m/z 184.3 (MH⁺); ¹H NMR (DMSO-d⁶): δ 8.04 (s, 3H), 7.36-7.34 (d, J = 5.07 Hz, 1H), 6.85-6.84 (d, J = 5.07 Hz, 1H), 4.76-4.74 (d,J = 7.38 Hz, 1H), 4.14-4.09 (m, 1H), 3.71-3.64 (m, 1H), 2.87-2.69 (m,4H), 2.24-2.15 (m, 1H), 2.00-1.88 (m, 1H). 65

HCl A LC-MS m/z 207.3 (MH⁺); ¹H NMR (DMSO-d⁶): δ 14.65 (s, 2H), 9.12 (s,1H), 7.50 (s, 1H), 7.40-7.38 (d, J = 5.20 Hz, 1H), 6.74-6.72 (d, J =5.20 Hz, 1H), 5.95 (s, 1H), 4.03- 3.85 (m, 2H), 2.98-2.84 (m, 2H). 66

HCl CS; FME of separation of Compound 21 on OJ with 2.5% MEHD ¹H NMR(CD₃OD): δ 7.26 (d, J = 5.0 Hz, 1H), 6.94 (d, J = 5.0 Hz, 1H), 4.00 (t,J = 5.1 Hz, 2H), 3.33- 3.21 (m, 3H), 3.08 (apt, J = 2.8 Hz, 1H), 2.87(t, J = 5.1 Hz, 2H), 2.18- 2.11 (m, 1H), 2.04-1.97 (m, 2H), 1.84-1.80(m, 1H). 67

HCl CS; SME of separation of Compound 21 on OJ with 2.5% MEHD ¹H NMR(CD₃OD): δ 7.26 (d, J = 5.0 Hz, 1H), 6.94 (d, J = 5.0 Hz, 1H), 4.00 (t,J = 5.1 Hz, 2H), 3.33- 3.21 (m, 3H), 3.08 (apt, J = 2.8 Hz, 1H), 2.87(t, J = 5.1 Hz, 2H), 2.18- 2.11 (m, 1H), 2.04-1.97 (m, 2H), 1.84-1.80(m, 1H). 68

HCl G ¹H NMR (CD₃OD): δ 6.40 (d, J = 2.0 Hz, 1H), 4.80 (dd, J = 3.0, 5.5Hz, 1H), 4.27-4.22 (m, 1H), 3.89- 3.83 (m, 1H), 3.37 (dd, J = 3.0, 13.0Hz, 1H), 3.11 (dd, J = 8.0, 13.0 Hz, 1H), 2.93-2.85 (m, 1H), 2.61 (dd, J= 2.0 16.0 Hz, 1H). 69

HCl G ¹H NMR (CD₃OD): δ 6.40 (d, J = 2.0 Hz, 1H), 4.86 (m, 1H), 4.28-4.23 (m, 1H), 3.90-3.84 (m, 1H), 3.45 (dd, J = 2.5, 13.0 Hz, 1H), 3.23(dd, J = 8.5, 13.0 Hz, 1H), 2.93-2.85 (m, 1H), 2.73 (s, 3H), 2.63 (dd, J= 2.0, 6.0 Hz, 1H). 70

HCl F LC-MS m/z 238.3 (MH⁺); ¹H NMR (CD₃OD): δ 6.57 (s, 1H), 5.03-5.00(d, J = 9.62 Hz, 1H), 4.30-4.23 (m, 1H), 3.89-3.55 (m, 4H), 3.46-3.38(m, 1H), 3.28-3.08 (m, 2H), 2.99- 2.89 (m, 1H), 2.75-2.70 (d, J = 16.44Hz, 1H), 2.43 (s, 3H), 2.25- 2.01 (m, 4H). 71

HCl F LC-MS m/z 252.3 (MH⁺); ¹H NMR (DMSO-d⁶): δ 10.36 (s, 1H), 6.68 (s,1H), 5.07-5.04 (d, J = 8.61 Hz, 1H), 4.15-4.08 (m, 1H), 3.82-3.66 (m,2H), 3.57-3.55 (m, 2H), 3.40- 3.30 (m, 1H), 3.17-3.01 (m, 2H), 2.86-2.68(m, 4H), 2.00-1.88 (m, 4H), 1.23-1.18 (t, J = 7.49 Hz, 3H). 72

HCl CS: FME of separation of Compound 17, on OJ with IHD 5 LC-MS (6 minmethod): broad peak at 0.23-0.67 minute, M⁺ 224 @ 0.56 min.; ¹H NMR(CD₃OD): δ 7.28 (d, J = 5.13 Hz, 1H), 6.94 (d, J = 5.13 Hz, 1H),5.15-5.12 (m, 1H), 4.30- 4.26 (m, 1II), 3.89-3.74 (m, 3II), 3.68-3.63(m, 1H), 3.44 (dd, J = 9.90, 12.8 Hz, 1H), 3.34-3.29 (m, 1H), 3.19-3.12(m, 1H), 3.04-2.99 (m, 1H), 2.84-2.79 (m, 1H), 2.24- 2.03 (m, 4H). 73

HCl CS: SME of separation of Compound 17, on OJ with IHD 5 LC-MS (6minute method on tab 209 instrument): broad peak at 0.23- 0.67 minute,M⁺ 224 @ 0.56 min.; ¹H NMR (CD₃OD): δ 7.28 (d, J = 5.13 Hz, 1H), 6.94(d, J = 5.13 Hz, 5.15-5.12 (m, 1H), 4.30-4.26 (m, 1H), 3.89-3.74 (m,3H), 3.68- 3.63 (m, 1H), 3.44 (dd, J = 9.90, 12.8 Hz, 1H), 3.34-3.29 (m,1H), 3.19-3.12 (m, 1H), 3.04-2.99 (m, 1H), 2.84-2.79 (m, 1H), 2.24-2.03(m, 4H). 74

HCl F LC-MS (6 min method): 2.24 minute, M⁺ 240 @ 2.25 min.; 1H NMR(CD₃OD): δ 7.30 (d, J = 5.13 Hz, 1H), 6.90 (d, J = 5.13 Hz, 1H), 5.24(dd, J = 2.57, 10.3 Hz, 1H), 4.31-4.27 (m, 1H), 4.12-4.03 (m, 2H),3.89-3.81 (m, 4H), 3.75 (dd, J = 2.93, 13.2 Hz, 1H), 3.70-3.66 (d, J =13.2 Hz, 1H), 3.55 (d, J = 12.5 Hz, 1H), 3.41-3.35 (m, 1H), 3.26- 3.22(m, 1H), 3.06-2.98 (m, 1H), 2.86-2.82 (m, 1H). 75

HCl CS; FME of SFC separation of Compound 10, using isocratic 18%[(25:75 MeOH:iPrOH (0.5% isopropylamine))] in CO₂ on a LC-MS (6 minutemethod); 1.6 min, M⁺ @ 1.71 min; ¹H NMR (CD₃OD): δ 6.59 (s, 1H), 4.91(d, J = 8.43 Hz, 1H), 4.27-4.22 (m, 1H), 3.84-3.78 (m, 1H), 3.50 (dd, J= 2.93, 12.8 Hz, 1H), 3.24-3.19 (m, 1H), 2.98-2.92 (m, 1H), 2.79 (q,2H), 2.80-2.68 (m, 1H), 2.73 (s, 3H), 1.27 (t, 3H). RegisPack 5 μ andflow of 80 g/min 76

HCl CS; SME of SFC separation of Compound 10, using isocratic 18%[(25:75 MeOH:iPrOH (0.5% isopropylamine))] in CO₂ on a LC-MS (6 minutemethod); 1.6 min, M⁺ 212 @ 1.71 min; ¹H NMR (CD₃OD): δ 6.59 (s, 1H),4.91 (d, J = 8.43 Hz, 1H), 4.27-4.22 (m, 1H), 3.84-3.78 (m, 1H), 3.50(dd, J = 2.93, 12.8 Hz, 1H), 3.24-3.19 (m, 1H), 2.98-2.92 (m, 1H), 2.79(q, 2II), 2.80-2.68 (m, 1II), 2.73 (s, 3H), 1.27 (t, 3H). RegisPack 5 μand flow of 80 g/min 77

HCl C ¹H NMR (CD₃OD): δ 7.10 (d, J = 5.5 Hz, 1H), 6.83 (d, J = 5.5 Hz,1H), 4.73 (dd, J = 3.5, 10.0 Hz, 1H), 4.33 (dt, J = 5.0, 12. 5 Hz, 1H),3.92-3.85 (m, 1H), 3.52 (dd, J = 3.0, 13.0 Hz, 1H), 3.25-3.19 (m, 1H),3.15-3.08 (m, 1H), 3.00-2.93 (m, 1H), 1.99-1.88 (m, 2H). 78

HCl A LC-MS m/z 198.3 (MH⁺); ¹H NMR (DMSO-d⁶): δ 9.11 (br s, 1H), 8.59(br s, 1H), 7.00 (s, 1H), 5.05-5.03 (d, J = 6.63 Hz, 1H), 4.04-3.96 (m,1H), 3.87-3.80 (m, 1H), 3.28-3.21 (m, 2H), 2.83-2.74 (m, 2H), 2.61- 2.59(d, J = 1.68 Hz, 3H), 2.13 (s, 3H). 79

HCl A LC-MS m/z 212.3 (MH⁺); ¹H NMR (DMSO-d⁶): δ 9.16 (br s, 1H), 8.58(s, 1H), 7.02 (s, 1H), 5.07-5.05 (d, J = 8.07 Hz, 1H), 4.05-3.97 (m,1H), 3.87-3.80 (m, 1H), 3.27-3.15 (m, 2H), 2.90-2.73 (m, 2H), 2.60 (s,3H), 2.47-2.41 (m, 2H), 1.22-1.17 (t, J = 7.40 Hz, 3H). 80

HCl A LC-MS m/z 226.0 (MH⁺); ¹H NMR (DMSO-d⁶): δ 8.99 (br s, 1H), 8.54(br s, 1H), 7.02 (s, 1H), 5.04-5.01 (d, J = 8.85 Hz, 1H), 4.05-3.97 (m,1H), 3.87-3.80 (m, 1H), 3.18 (s, 2H), 2.90-2.72 (m, 2H), 2.61 (s, 3H),2.46-2.40 (t, J = 7.80 Hz, 2H), 1.67-1.55 (m, 2H), 0.97-0.92 (t, J =7.31 Hz, 3H). 81

HCl A LC-MS m/z 260.3 (MII⁺); 1II NMR (CD₃OD): δ 7.55-7.39 (m, 5H), 7.23(s, 1H), 5.41-5.38 (m, 1H), 4.28- 4.21 (m, 1II), 3.98-3.90 (m, 1II),3.11-3.01 (m, 1H), 2.96-2.92 (m, 2H), 2.80-2.75 (dd, J₁ = 3.3 Hz, J₂ =12.9 Hz, 1H), 2.47 (s, 3H). 82

HCl A LC-MS m/z 212.3 (MH⁺); ¹H NMR (DMSO-d⁶): δ 9.10 (br s, 1H), 8.57(br s, 1H), 4.98-4.95 (d, J = 8.28 Hz, 1H), 4.03-3.95 (m, 1H), 3.85-3.78 (m, 1H), 3.21-3.17 (m, 2H), 2.79-2.65 (m, 2H), 2.60 (s, 3H), 2.25(s, 3H), 1.99 (s, 3H). 83

HCl C ¹H NMR (CD₃OD): δ 7.10 (d, J = 5.0 Hz, 1H), 6.84 (d, J = 5.0 Hz,1H), 4.82 (dd, J = 3.0, 10.5 Hz, 1H), 4.33 (dt, J = 4.5, 12.5 Hz, 1H),3.93- 3.86 (m, 1H), 3.59 (dd, J = 2.5, 12.5 Hz, 1H), 3.39-3.33 (m, 1H),3.15- 3.08 (m, 1H), 3.01-2.80 (m, 1H), 2.78 (s, 3H), 1.99-1.88 (m, 2H).84

HCl CS; FME of separation of Compound 63 on AS with IHD 10 ¹H NMR(CD₃OD): δ 6.59 (s, 1H), 3.97 (t, J = 5.0 Hz, 2H), 3.33-3.24 (m, 3H),3.05 (dt, J = 3.0, 13.0 Hz, 1H), 2.77 (t, J = 5.0 Hz, 2H), 2.41 (s, 3H),2.16-2.08 (m, 1H), 2.00- 1.88 (m, 2H), 1.80 (d, J = 14.0 Hz, 1H). 85

HCl CS; SME of separation of Compound 63 on AS with IHD 10 ¹H NMR(CD₃OD): δ 6.59 (s, 1H), 3.97 (t, J = 5.0 Hz, 2H), 3.33-3.24 (m, 3H),3.05 (dt, J = 3.0, 13.0 Hz, 1H), 2.77 (t, J = 5.0 Hz, 2H), 2.41 (s, 3H),2.16-2.08 (m, 1H), 2.00- 1.88 (m, 2H), 1.80 (d, J = 14.0 Hz, 1H). 86

HCl F LC-MS (6 minute method): 1.85 min, M⁺ 221 @ 1.83 min; ¹H NMR(CD₃OD): δ 8.91 (s, 1H), 7.57 (s, 1H), 7.49 (s, 1H), 7.29 (d, J = 5.13Hz, 1H), 7.09 (d, J = 5.50 Hz, 1H), 5.13-5.10 (m, 1H), 4.80 (dd, J =2.57, 14.3 Hz, HD, 4.60 (dd, J = 6.60, 14.3 Hz, 1H), 4.26-4.22 (m, 1H),3.79-3.73 (m, 1H), 2.87-2.79 (m, 1H), 2.74-2.70 (m, 1H). 87

HCl H ¹H NMR (CD₃OD): δ 4.64 (dd, J = 3.0. 9.5 Hz, 1H), 4.23 (dd, J =3.5, 11.5 Hz, 1H), 4.16-4.08 (m, 2H), 3.87 (td, J = 1.5, 12.0 Hz, 1H),3.82- 3.78 (m, 2H), 3.68 (dd, J = 2.5, 13.0 Hz, 1H), 3.40 (dd, J = 9.5,13.0 Hz, 1H), 3.30 (bs, 1H), 2.74 (d, J = 13.0 Hz, 1H), 2.29-2.20 (m,4H), 1.96- 1.89 (td, J = 5.0, 12.5 Hz, 1H). 88

HCl H LC-MS (6 min method): 0.28 minute, M⁺ 213 @ 0.33 min.; ¹H NMR(CD₃OD): δ 4.61 (dd, J = 3.0, 10.0 Hz, 1H), 4.26-4.20 (m, 1H), 3.86 (td,J = 2.0, 12.5 Hz, 1H), 3.69 (s, 3H), 3.66 (d, J = 2.0 Hz, 1H), 3.57 (s,3H), 3.45-3.35 (m, 1H), 3.13-2.97 (m, 1H), 2.74 (d, J = 13.0 Hz, 1H),1.92 (td, J = 4.0, 13.0 Hz, 1H). 89

HCl B LC-MS (6 min method): 0.27-0.45 min, M⁺ 184 @ 0.38 min; ¹H NMR(CD₃OD): δ 7.36 (d, J = 4.76 Hz, 1H), 6.90 (d, J = 5.13 Hz, 1H), 5.16(d, J = 8.06 Hz, 1H), 4.28-4.23 (m, 1H), 3.85-3.79 (m, 1H), 3.51-3.47(m, 1H), 3.26-3.23 (m, 1H), 2.86- 2.82 (m, 1H), 2.75 (s, 3H), 2.71- 2.66(m, 1H). 90

HCl F LC-MS (6 min method): 1.37 min, M⁺ 226 @ 1.44 min; ¹H NMR (CD₃OD):δ 6.60 (s, 1H), 4.94-4.91 (m, 1H), 4.26-4.21 (m, 1H), 3.84- 3.78 (m,1H), 3.50 (dd, J = 2.2, 12.8 Hz, 1H), 3.19-3.09 (m, 3H), 2.93- 2.89 (m,1H), 2.81-2.69 (m, 3H), 1.33 (t, 3H), 1.27 (t, 3H). 91

HCl A LC-MS m/z 224.3 (MH⁺); ¹H NMR (DMSO-d⁶ + D₂O): δ 6.75 (s, 1II),3.90-3.85 (m, 2H), 3.45-3.41 (m, 2H), 3.26-3.22 (m, 2H), 2.77-2.69 (m,4H), 2.23-2.18 (m, 2H), 1.22- 1.17 (t, J = 7.52 Hz, 3H). 92

HCl A LC-MS m/z 238.3 (MH⁺); ¹H NMR (DMSO-d⁶): δ 9.04 (br s, 1H), 8.31(s, 1H), 6.76 (s, 1H), 3.93-3.89 (t, J = 5.10 Hz, 2H), 3.25-3.15 (m,3H), 2.93-2.90 (m, 1H), 2.81-2.70 (m, 4H), 1,94-1.80 (m, 3H), 1.69-1.67(m, 1H), 1.24-1.19 (t, J = 7.52 Hz, 3H). 93

HCl D ¹H NMR (CD₃OD): δ 7.23 (d, J = 2.0 Hz, 1H), 7.14 (d, J = 2.5 Hz,1H), 4.93 (d, J = 7.0 Hz, 1H), 4.24- 4.19 (m, 1H), 3.71 (td, J = 4.0,11.0 Hz, 1H), 3.52 (dd, J = 2.5, 13.0 Hz, 1H), 3.19 (dd, J = 7.5, 13.0Hz, 1H), 2.96-2.87 (m, 1H), 2.81-2.75 (m, 1H). 94

HCl CS; FME of separation of Compound 30, on AD column with MEHD 5 LC-MS(6 min method): 0.49-1.01 min, M⁺ 198 @ 0.73 mm; ¹H NMR (DMSO-d⁶): δ8.06 (br s, 1H), 7.02 (s, 1H), 4.97-4.93 (dd, J₁ = 3.5 Hz, J₂ = 9.1 Hz,1H), 4.03-3.95 (m, 1H), 3.86-3.79 (m, 1H), 3.09 (br s, 2H), 2.84-2.73(m, 2H), 2.47-2.37 (m, 2H), 1.21-1.17 (t, J = 7.41 Hz, 3H). 95

HCl CS; SMF, of separation of Compound 30, on AD column with MEHD 5LC-MS (6 min method): 0.49-1.01 min, M⁺ 198 @ 0.73 min; ¹H NMR(DMSO-d⁶): δ 8.06 (br s, 1H), 7.02 (s, 1H), 4.97-4.93 (dd, J₁ = 3.5 Hz,J₂ = 9.1 Hz, 1H), 4.03-3.95 (m, 1H), 3.86-3.79 (m, 1H), 3.09 (br s, 2H),2.84-2.73 (m, 2H), 2.47-2.37 (m, 2H), 1.21-1.17 (t, J = 7.41 Hz, 3H). 96

HCl K LC-MS (6 min method): 0.37 mm, M⁺ 187 @ 0.35 min.; ¹II NMR(CD₃OD): δ 7.27 (d, J = 5.13 Hz, 1H), 6.87 (d, J = 5.13 Hz, 1H), 4.98(d, J = 8.43 IIz, 1II), 4.28-4.23 (m, 1H), 3.84-3.78 (m, 1H), 3.54-3.51(m, 1H), 3.22 (dd, J = 8.43, 12.8 Hz, 1H), 3.03-2.95 (m, 1H), 2.80 (d, J= 16.1 Hz, 1H). 97

HCl D ¹H NMR (CD₃OD): δ 7.20 (d, J = 2.0 Hz, 1H), 7.13 (d, J = 2.5 Hz,1H), 4.96 (d, J = 7.0 Hz, 1H), 4.23- 4.19 (m, 1H), 3.70 (td, J = 4.0,11.0 Hz, 1H), 3.49 (dd, J = 3.0, 13.0 Hz, 1H), 3.22 (dd, J = 8.5, 13.0Hz, 1H), 2.936-2.86 (m, 1H), 2.81-2.75 (m, 1H), 2.69 (s, 3H). 98

HCl C ¹H NMR (CD₃OD): δ 6.50 (s, 1H), 4.66 (dd, J = 2.5, 0.7 Hz, 1H),4.30 (dt, J = 2.5, 1.2 Hz, 1H), 3.85 (ddd, J = 3.0, 2.5, 1.2 Hz, 1H),3.46 (dd, J = 3.0, 0.7 Hz, 1H), 3.33-3.29 (m, 1H), 3.17 (dd, J = 3.0,2.5 Hz, 1H), 3.00 (ddd, J = 4.0, 2.0, 0.7 Hz, 1H), 2.86 (ddd, J = 4.0,2.0, 0.7 Hz, 1H), 2.37 (s, 3H), 1.96-1.86 (m, 2H). 99

HCl C ¹H NMR (CD₃OD): δ 6.51 (s, 1H), 4.74 (dd, J = 2.5, 0.8 Hz, 1H),4.30 (dt, J = 3.0, 1.5 Hz, 1H), 3.86 (ddd, J = 3.0, 2.0, 1.0 Hz, 1H),3.53 (dd, J = 3.0, 1.0 Hz, 1H), 3.01 (ddd, J = 4.0, 2.0, 1.0 Hz, 1H),2.87 (ddd, J = 4.0, 2.0, 1.0 Hz, 1H), 2.76 (s, 3H), 2.37 (s, 3H),1.98-1.85 (m, 2H). 100

HCl C ¹H NMR (CD₃OD): δ 6.53 (s, 1H), 4.66 (dd, J = 2.5, 0.7 Hz, 1H),4.30 (dt, J = 3.0, 1.2 Hz, 1H), 3.85 (ddd, J = 3.2, 2.7, 1.2 Hz, 1H),3.48 (dd, J = 3.2, 0.7 Hz, 1H), 3.17 (dd, J = 3.2, 2.7 Hz, 1H), 3.03(ddd, J = 4.0, 2.0, 1.0 Hz, 1H), 2.88 (ddd, J = 4.0, 2.0, 1.0 Hz, 1H),2.74 (q, J = 1.9 Hz, 2H), 1.96-1.88 (m, 2H), 1.24 (t, J = 3H). 101

HCl C ¹H NMR (CD₃OD): δ 6.54 (s, 1H), 4.75 (dd, J = 2.5, 0.7 Hz, 1H),4.31 (dt, J = 3.0, 1.2 Hz, 1H), 3.86 (ddd, J = 3.2, 2.2, 1.0 Hz, 1H),3.55 (dd, J = 3.0, 0.7 Hz, 1H), 3.34-3.28 (m, 1H), 3.02 (ddd, J = 4.0,2.0, 1.0 Hz, 1H), 2.89 (ddd, J = 4.0, 2.0, 1.0 Hz, 1H), 2.77 (s, 3H),2.74 (q, J = 1.9 Hz, 2H), 1.98-1.86 (m, 2H), 1.25 (t, J = 1.9 Hz, 3H).102

HCl N LC-MS: m/z 210 (MH⁺); ¹H NMR (DMSO-d₆): δ 10.05 (s, 1H), 8.79 (s,1H), 7.41-7.39 (d, J = 5.19 Hz, 1H), 6.99-6.98 (d, J = 5.22 Hz, 1H),5.06-5.05 (d, J = 2.10 Hz, 1H), 4.28-4.17 (m, 2H), 3.75-3.67 (m, 1H),3.22-3.05 (m, 2H), 2.96-2.90 (m, 1H), 2.79-2.73 (m, 1H), 1.91- 1.74 (m,2H), 1.65-1.55 (m, 2H). 103

HCl N LC-MS: m/z 210 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.69 (s, 1H), 8.51 (s,1H), 7.41-7.40 (d, J = 4.50 Hz, 1H), 6.97-6.96 (d, J = 4.20 Hz, 1H),4.89-4.88 (d, J = 4.20 Hz, 1H), 4.19-4.15 (m, 1H), 3.92-3.90 (m, 1H),3.76 (s, 1H), 3.10-2.95 (m, 3H), 2.80-2.75 (m, 1H), 2.14-1.84 (m, 4H).104

HCl N LC-MS: m/z 184 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.39 (s, 3H), 7.40- 7.38(d, J = 5.16 Hz, 1H), 6.99-6.98 (d, J = 5.22 Hz, 1H), 4.99-4.98 (d, J =1.78 Hz, 1H), 4.27-4.22 (dd, J = 11.24 Hz, 5.12 Hz, 1H), 3.82 (s, 1H),3.70-3.62 (m, 1H), 2.98-2.87 (m, 1H), 2.77-2.71 (m, 1H), 0.91- 0.89 (d,J = 6.69 Hz, 3H). 105

HCl N LC-MS: m/z 184 (MH⁺); ¹H NMR (DMSO-d₆): δ 7.84 (s, 3H), 7.41- 7.40(d, J = 5.10 Hz, 1H), 7.00-6.98 (d, J = 5.10 Hz, 1H), 4.71-4.70 (d, J =2.11 Hz, 1H), 4.20-4.13 (m, 1H), 3.77-3.69 (m, 2H), 2.95-2.76 (m, 2H),1.36-1.34 (d, J = 6.6 Hz, 3H). 106

HCl N LC-MS: m/z 212 (MH⁺); ¹H NMR (DMSO-d₆): δ 7.59 (s, 3H), 7.43-7.41(d, J = 5.40 Hz, 1H), 7.01-6.99 (d, J = 5.10 Hz, 1H), 4.95 (s, 1H),4.24-4.18 (m, 1H), 3.77- 3.68 (m, 1H), 2.95-2.91 (m, 1H), 2.77-2.72 (m,1H), 2.12-2.05 (m, 1H), 1.06-1.03 (m, 6H). 107

HCl N LC-MS: m/z 212 (MH⁺); ¹H NMR (CD₃OD): δ 7.33-7.31 (d, J = 5.40 Hz,1H), 6.93-6.91 (d, J = 7.56 Hz, 1H), 5.08-5.06 (m, 1H), 4.39- 4.33 (m,1H), 3.76-3.67 (m, 1H), 3.53-3.51 (m, 1H), 3.10-3.07 (m, 1H), 2.81-2.75(m, 1H), 2.08-2.01 (m, 1H), 1.04-0.97 (m, 6H). 108

HCl O LC-MS: m/z 198 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.16 (s, 3H), 7.41- 7.40(d, J = 5.28 Hz, 1H), 6.98-6.97 (d, J = 5.22 Hz, 1H), 4.80 (s, 1H),4.25-4.20 (m, 1H), 3.58-3.50 (dd, J = 10.85 Hz, 3.20 Hz, 1H), 2.96-2.74(m, 2H), 1.48 (s, 3H), 1.01 (s, 3H). 109

HCl O LC-MS: m/z 212 (MH⁺); ¹H NMR (CD₃OD): δ 7.34-7.32 (dd, J = 5.03Hz, 5.03 Hz, 1H), 6.98-6.96 (d, J = 5.34 Hz, 1H), 4.98-4.97 (m, 1H),4.38-4.32 (m, 1H), 3.71-3.62 (td, J = 11.13 Hz, 2.94 Hz, 1H), 3.03-2.97(m, 1H), 2.84-2.78 (m, 1H), 2.69 (s, 3H), 1.59 (s, 3H), 1.14 (s, 3H).110

HCl O LC-MS: m/z 196 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.25-8.21 (brs, 3H),7.40-7.39 (d, J = 5.10 Hz, 1H), 7.25-7.23 (d, J = 5.40 Hz, 1H),4.10-4.03 (m, 2H), 3.90-3.82 (m, 1H), 2.93-2.73 (m, 2H), 2.29-2.21 (m,2H), 2.18-2.02 (m, 2H). 111

HCl O LC-MS: m/z 210 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.03 (s, 2H), 7.41-7.40(d, J = 4.51 Hz, 1H), 7.22-7.20 (d, J = 3.92 Hz, 1H), 4.13-4.04 (m, 2H),3.86-3.79 (m, 1H), 2.96-2.91 (m, 1H), 2.78-2.73 (m, 1H), 2.31 (s, 3H),2.26-2.01 (m, 4H). 112

HCl O LC-MS: m/z 210 (MH⁺); ¹H NMR (DMSO-d₆): δ 7.86 (s, 3H), 7.37- 7.36(d, J = 5.10 Hz, 1H), 7.05-7.04 (d, J = 5.31 Hz, 1H), 4.10-4.05 (dd, J =11.49 Hz, 4.71 Hz, 1H), 3.81- 3.71 (m, 2H), 2.98-2.87 (m, 1H), 2.89-2.87(m, 1H), 2.17-2.10 (m, 2H), 1.88-1.82 (m, 4H). 113

HCl O LC-MS: m/z 224 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.20(s, 1H), 8.17(s,1H), 7.40-7.38 (d, J = 5.1 Hz, 1H), 7.06-7.05 (d, J = 5.4 Hz, 1H),4.13-4.07 (m, 1H), 3.84-3.70 (m, 2H), 3.02-2.89 (m, 1H), 2.77- 2.71 (m,1H), 2.26-2.16 (m, 5H), 1.89-1.80 (m, 4H). 114

HCl O LC-MS: m/z 224 (M1-1+30); ¹H NMR (DMSO-d₆): δ 7.85 (s, 3H), 7.41-7.39 (d, J = 4.82 Hz, 1H), 7.00-6.98 (d, J = 4.83 Hz, 1H), 4.85 (s, 1H),4.23-4.17 (m, 1H), 3.61-3.54 (t, J = 10.24 Hz, 1H), 3.01-2.92 (m, 1H),2.79-2.74 (m, 1H), 2.17-2.12 (m, 1H), 1.87-1.77 (m, 5H), 1.54 (s, 2H).115

HCl O LC-MS: m/z 238 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.66 (s, 2H), 7.41- 7.40(d, J = 3.95 Hz, 1H), 7.00-9.99 (d, J = 3.96 Hz, 1H), 5.03 (s, 1H),4.20-4.17 (m, 1H), 3.62-3.55 (m, 1H), 2.93-2.82 (m, 1H), 2.76-2.74 (m,1H), 2.50 (s, 3H), 2.20-2.15 (m, 1H), 1.96-1.89 (m, 1H), 1.74-1.61 (m,4H), 1.49-1.38 (m, 2H). 116

HCl O LC-MS: m/z 238 (MH⁺); ¹H NMR (DMSO-d₆): δ 7.73 (s, 3H), 7.43- 7.41(d, J = 4.84 Hz, 1H), 6.97-6.95 (d, J = 4.85 Hz, 1H), 4.94 (s, 1H),4.22-4.19 (m, 1H), 3.57-3.51 (m, 1H), 2.98-2.90 (m, 1H), 2.78-2.74 (m,1H), 1.94-1.91 (m, 1H), 1.77- 1.42 (m, 8H), 1.26 (s, 1H). 117

HCl O LC-MS: m/z 252 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.47 (s, 1H), 8.36 (s,1H), 7.45-7.44 (d, J = 4.88 Hz, 1H), 6.99-6.97 (d, J = 1.86 Hz, 1H),5.05 (s, 1H), 4.24-4.19 (m, 1H), 3.58-3.51 (m, 1H), 2.97-2.90 (m, 1H),2.80-2.75 (m, 1H), 2.34 (s, 3H), 1.95-1.32 (m, 10H). 118

HCl N LC-MS: m/z 210 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.48-9.47 (d, J = 2.07Hz, 1H), 8.40-8.39 (d, J = 3.54 Hz, 1H), 7.42-7.40 (d, J = 3.54 Hz, 1H),6.98-6.96 (d, J = 5.22 Hz, 1H), 4.89-4.87 (d, J = 5.31 Hz, 1H),4.22-4.15 (m, 1H), 3.95-3.89 (m, 1H), 3.80-3.72 (m, 1H), 3.13-3.06 (m,2H), 2.97-2.75 (m, 1H), 2.50- 2.49 (m, 1H), 2.13-1.84 (m, 4H). 119

HCl N LC-MS: m/z 210 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.94 (s, 1H), 8.76-8.75(d, J = 4.20 Hz, 1H), 7.41-7.39 (d, J = 5.19 Hz, 1H), 6.99-6.98 (d, J =5.22 Hz, 1H), 5.05-5.04 (d, J = 2.07 Hz, 1H), 4.28-4.15 (m, 2H),3.75-3.70 (m, 1H), 3.20-3.10 (m, 2H), 2.96-2.92 (m, 1H), 2.79-2.73 (m,1H), 1.90- 1.56 (m, 4H). 120

HCl P LC-MS: m/z 202 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.19 (s, 3H), 4.89- 4.86(d, J = 7.25 Hz, 1H), 4.06-4.00 (m, 1H), 3.98-3.79 (m, 1H), 3.16- 3.06(m, 2H), 2.76-2.62 (m, 2H), 1.99-1.98 (d, J = 2.14 Hz, 3H). 121

HCl P LC-MS: m/z 216 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.25 (s, 1H), 8.67 (s,1H), 5.00-4.97 (d, J = 8.10 Hz, 1H), 4.08-4.00 (m, 1H), 3.88-3.79 (m,1H), 3.41-3.14 (m, 2H), 2.77- 2.65 (m, 5H), 2.01-2.00 (d, J = 2.10 Hz,3H). 122

HCl P LC-MS: m/z 216 (MH⁺); ¹H NMR (CD₃OD): δ 4.91-4.85 (m, 1H),4.20-4.12 (m, 1H), 3.91-3.84 (m, 1H), 3.29-3.17 (m, 2H), 2.79-2.72 (m,2H), 2.57-2.43 (m, 2H), 1.22- 1.15 (m, 3H). 123

HCl P LC-MS: m/z 230 (MII⁺); ¹H NMR (CD₃OD): δ 4.98-4.94 (m, 1H),4.22-4.14 (m, 1H), 3.92-3.84 (m, 1H), 3.36-3.33 (m, 2H), 2.80-2.69 (m,5H), 2.62-2.51 (m, 1H), 2.50- 2.35 (m, 1H), 1.22-1.17 (t, J = 7.55 Hz,3H). 124

HCl D ¹H NMR (CD₃OD): δ 7.2() (d, J = 2.0 Hz, 1H), 7.13 (d, J = 2.5 Hz,1II), 4.96 (d, J = 7.0 Hz, 2II), 4.23- 4.19 (m, 1H), 3.70 (td, J = 4.0,11.0 Hz, 1H), 3.49 (dd, J = 3.0, 13.0 Hz, 1H), 3.22 (dd, J = 8.5, 13.0Hz, 1H), 2.94-2.86 (m, 1H), 2.81-2.75 (m, 1H) 2.69 (s, 3H). 125

HCl A LC-MS (6 minute method): 1.17 min, M⁺ 207 @ 1.1 min; ¹H NMR(CD₃OD-d⁴): δ 7.61 (s, 1H), 7.16 (d, J = 4.76 Hz, 1H), 7.03 (s, 1H),6.81 (d, J = 5.13 Hz, 1H), 5.94 (s, 1H), 4.16-4.12 (m, 1H), 3.93-3.86(m, 1H), 2.87-2.80 (m, 1H), 2.74- 2.68 (m, 1H). 126

HCl CS; FME from SFC separation of Compound 36, using isocratic 15%Methanol in CO₂ on a 4.6 × 100 mm LUX ¹H NMR (CD₃OD): δ 7.34 (d, J =5.13 Hz, 1H), 6.89 (d, J = 5.13 Hz, 1H), 5.06 (s, 1H), 4.25-4.22 (m,1H), 3.83-3.77 (m, 1H), 3.38 (d, J = 13.2 Hz, 1H), 3.16-3.12 (m, 1H),2.85-2.83 (m, 1H), 2.68-2.65 (m, 1H). Cellulose 2 from Phenomenex andflow of 4 mL/min 127

HCl CS; SME from SFC separation of Compound 36, using isocratic 15%Methanol in CO₂ on a 4.6 × 100 mm LUX ¹H NMR (CD₃OD): δ 7.34 (d, J =5.13 Hz, 1H), 6.89 (d, J = 5.13 Hz, 1II), 5.06 (s, 1II), 4.25-4.22 (m,1H), 3.83-3.77 (m, 1H), 3.38 (d, J = 13.2 Hz, 1H), 3.16-3.12 (m, 1H),2.85-2.83 (m, 1H), 2.68-2.65 (m, 1H). Cellulose 2 from Phenomenex andflow of 4 mL/min 128

HCl CS; FME from SFC separation of Boc- protected Compound 89, usingisocratic 15% isopropanol in CO₂ on a 4.6 × 100 mm LUX ¹H NMR (CD₃OD): δ7.36 (d, J = 5.13 Hz, 1H), 6.89 (d, J = 4.76 Hz, 1H), 5.14-5.11 (m, 1H),4.27-4.22 (m, 1H), 3.84-3.77 (m, 1H), 3.49- 3.45 (m, 1H), 3.26-3.23 (m,1H), 2.89-2.81 (m, 1H), 2.73 (s, 3H), 2.70-2.64 (m, 1H). Cellulose 2from Phenomenex and flow of 80 g/min 129

HCl CS; SME from SFC separation of Boc- protected Compound 89, usingisocratic 15% isopropanol in CO₂ on a 4.6 × 100 mm LUX ¹H NMR (CD₃OD): δ7.36 (d, J = 5.13 Hz, 1H), 6.89 (d, J = 4.76 Hz, 1H), 5.14-5.11 (m, 1H),4.27-4.22 (m, 1H), 3.84-3.77 (m, 1H), 3.49- 3.45 (m, 1H), 3.26-3.23 (m,1H), 2.89-2.81 (m, 1H), 2.73 (s, 3H), 2.70-2.64 (m, 1H). Cellulose 2from Phenomenex and flow of 80 g/min 130

HCl CS; FME from SFC separation of Boc- protected Compound 78, usingisocratic 43% (hexane: isopropanol 99:1) in CO₂ on a 4.6 × 100 mm ¹H NMR(DMSO-d⁶): δ 9.11 (br s, 1H), 8.59 (br s, 1H), 7.00 (s, 1H), 5.05-5.03(d, J = 6.63 Hz, 1H), 4.04-3.96 (m, 1H), 3.87-3.80 (m, 1H), 3.28-3.21(m, 2H), 2.83-2.74 (m, 2H), 2.61-2.59 (d, J = 1.68 Hz, 3H), 2.13 (s,3H). Whelk-O1 from Regis and flow of 80 g/min 131

IICl CS; SME from SFC separation of Boc- protected Compound 78, usingisocratic 43% (hexane: isopropanol 99:1) in CO₂ on a 4.6 × 100 mm ¹H NMR(DMSO-d₆): δ 9.11 (br s, 1H), 8.59 (br s, 1H), 7.00 (s, 1H), 5.05-5.03(d, J = 6.63 Hz, 1H), 4.04-3.96 (m, 1H), 3.87-3.80 (m, 1H), 3.28-3.21(m, 2H), 2.83-2.74 (m, 2II), 2.61-2.59 (d, J = 1.68 IIz, 3H), 2.13 (s,3H). Whelk-O1 from Regis and flow of 80 g/min 132

HCl CS; FME from SFC separation of Compound 79, using isocratic 10%Hexane: Isopropanol (1:1) in CO₂ on a 4.6 x 100 mm LUX Cellulose ¹H NMR(DMSO-d₆): δ 9.16 (br s, 1H), 8.58 (s, 1H), 7.02 (s, 1H), 5.07-5.05 (d,J = 8.07 Hz, 1H), 4.05-3.97 (m, 1H), 3.87-3.80 (m, 1H), 3.27-3.15 (m,2H), 2.90-2.73 (m, 2H), 2.60 (s, 3H), 2.47-2.41 (m, 2H), 1.22-1.17 (t, J= 7.40 Hz, 3H). 2 from Phenomenex and flow of 4 mL/min 133

HCl CS; SME from SFC separation of Compound 79, using isocratic 10%Hexane: Isopropanol (1:1) in CO₂ on a 4.6 × 100 mm LUX Cellulose ¹H NMR(DMSO-d₆): δ 9.16 (br s, 1H), 8.58 (s, 1H), 7.02 (s, 1H), 5.07-5.05 (d,J = 8.07 Hz, 1H), 4.05-3.97 (m, 1H), 3.87-3.80 (m, 1H), 3.27-3.15 (m,2H), 2.90-2.73 (m, 2H), 2.60 (s, 3H), 2.47-2.41 (m, 2H), 1.22-1.17 (t, J= 7.40 Hz, 3H). 2 from Phenomenex and flow of 4 mL/min 134

HCl B LC-MS: m/z 184 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.15 (s, 3H), 6.61 (s,1H), 4.98-4.96 (d, J = 8.10 Hz, 1H), 4.12-4.03 (m, 1H), 3.77-3.66 (m,1H), 3.23-3.14 (m, 1H), 2.98 (s, 1H), 2.85-2.62 (m, 2H), 2.40 (s, 3H).135

HCl B LC-MS: m/z 198 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.17 (s, 1H), 8.75 (s,1H), 6.62-6.61 (s, J = 0.95 Hz, 1H), 4.13-4.06 (m, 1H), 5.09-5.06 (d, J= 9.06 Hz, 1H), 3.78-3.70 (m, 1H), 3.30-3.08 (m, 2H), 2.69-2.52 (m, 5H),2.40 (s, 3H). 136

HCl B LC-MS: m/z 198 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.23 (s, 3H), 6.65 (s,1H), 5.00-4.97 (d, J = 7.85 Hz, 1H), 4.13-4.06 (m, 1H), 3.77-3.69 (m,1H), 3.16-3.11 (m, 1H), 3.03-2.93 (m, 1H), 2.79-2.70 (m, 2H), 2.67- 2.58(m, 2H), 1.23-1.18 (t, J = 7.50 Hz, 3H). 137

HCl B LC-MS: m/z 212 (MH⁺); ¹H NMR (DMSO-d₆ + D₂O): δ 6.64 (s, 1H),5.02-5.00 (d, J = 7.82 Hz, 1H), 4.10-4.05 (m, 1H), 3.77-3.69 (m, 1H),3.31-3.26 (m, 1H), 3.18-3.11 (m, 1H), 2.78-2.70 (m, 2H), 2.66- 2.63 (m,5H), 1.21-1.16 (t, J = 7.56 Hz, 3H). 138

HCl B LC-MS: m/z 202 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.31-9.29 (d, J = 6.24Hz, 1H), 8.85 (s, 1H), 6.59 (s, 1H), 5.06-5.03 (d, J = 8.79 Hz, 1H),4.13-4.09 (m, 1H), 3.81-3.79 (m, 1H), 3.25-3.20 (m, 2H), 2.72-2.57 (m,5H). 139

HCl B LC-MS: m/z 184 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.06 (s, 3H), 7.10 (s,1H), 5.02-4.99 (d, J = 8.93 Hz, 1H), 4.19-1.13 (m, 1H), 3.80-3.72 (m,1H), 3.22-3.14 (m, 1H), 2.99-2.89 (m, 1H), 2.65-2.60 (m, 2H), 2.05 (s,3H). 140

HCl B LC-MS: m/z 198 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.87 (s, 2H), 7.11 (s,1H), 5.11-5.08 (d, J = 9.64 Hz, 1H), 4.02-4.13 (m, 1H), 3.82-3.74 (m,1H), 3.35 (s, 1H), 3.20-3.12 (m, 1H), 2.60-2.50 (m, 5H), 2.09 (s, 3H).141

HCl B LC-MS: m/z 198 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.21 (s, 3H), 7.10 (s,1H), 5.03-5.00 (d, J = 8.15 Hz, 1H), 4.18-4.12 (m, 1H), 3.80-3.72 (m,1H), 3.20-3.18 (m, 1H), 2.99 (s, 1H), 2.68-2.60 (m, 3H), 2.45-2.43 (m,1H), 1.18-1.14 (t, J = 7.59 Hz, 3H). 142

HCl B LC-MS: m/z 212 (MH⁺); ¹H NMR (DMSO-d₆ + D₂O): δ 7.08 (s, 1H), 5.05(d, J = 10 Hz, 1H), 4.21-4.11 (m, 1H), 3.80-3.65 (m, 2H), 3.35- 3.12 (m,2H), 2.67-2.35 (m, 6H), 1.19-1.14 (t, J = 7.49 Hz, 3H). 143

HCl Z ¹H NMR (CD₃OD): δ 7.20 (d, J = 1.5 Hz, 1H), 6.90 (d, J = 1.5 Hz,1H), 3.33-3.30 (m, 1H), 3.08 (m, 1H), 2.99 (dd, J = 2.5, 3.0 Hz, 1H),2.80 (apt, J = 1.5 Hz, 2H), 2.02-1.87 (m, 2H), 1.85-1.81 (m, 1H), 1.71-1.64 (m, 1II). 144

HCl Z ¹H NMR (CD₃OD): δ 7.21 (d, J = 1.5 IIz, 1II), 6.92 (d, J = 1.5IIz, 1H), 3.36 (dd, J = 3.0, 1.0 Hz, 1H), 3.14 (m, 1H), 3.09 (dd, J =3.0, 2.5 Hz, 1H), 2.80 (apt, J = 1.5 Hz, 2H), 2.75 (s, 3H), 2.03-1.95(m, 2H), 1.88-1.81 (m, 1H), 1.72-1.65 (m, 1H). 145

HCl Q LC-MS: m/z 154 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.10-7.98 (d, J = 9.68Hz, 2H), 7.39-7.38 (d, J = 3.95 Hz, 1H), 6.98-6.96 (d, J = 5.10 Hz, 1H),3.35-3.30 (m, 1H), 3.16-3.11 (m, 1H), 2.97-2.79 (m, 3H), 2.70- 2.61 (m,1H), 2.27-2.22 (m, 1H). 146

HCl Q LC-MS: m/z 168 (MH⁺); ¹H NMR (CD₃OD): δ 7.33-7.31 (d, J = 4.20 Hz,1H), 6.91-6.90 (d, J = 4.52 Hz, 1H), 3.49-3.32 (m, 2H), 3.11- 2.80 (m,4H), 2.76 (s, 3H), 2.35- 2.24 (m, 1H). 147

HCl R LC-MS: m/z 228 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.56-9.53 (d, J = 7.21Hz, 1H), 8.38-8.29 (m, 1H), 6.76-6.75 (d, J = 2.46 Hz, 1H), 3.96-3.92(t, J = 5.45 Hz, 2H), 3.33- 3.13 (m, 3H), 2.87-2.81 (m, 1H), 2.74-2.62(m, 2H), 1.93-1.83 (m, 3H), 1.72-1.67 (m, 1H). 148

HCl R LC-MS: m/z 214 (MH⁺); ¹H NMR (CD₃OD): δ 9.90 (s, 1H), 9.40 (s,1H), 6.80-6.79 (d, J = 2.42 Hz, 1H), 3.98-3.86 (t, J = 5.51 Hz, 2H),3.44- 3.39 (m, 2H), 2.30-3.21 (m, 2H), 2.71-2.67 (t, J = 5.01 Hz, 2H),2.26- 2.21 (m, 2H). 149

HCl T LC-MS: m/z 218 (MH⁺); ¹H NMR (D₂O): δ 7.35-7.30 (m, 2H), 7.16-7.11 (m, 1H), 6.97-6.87 (m, 3H), 5.65-5.63 (m, 1H), 3.33-3.31 (m, 3H).150

HCl T LC-MS: m/z 232 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.25 (s, 1H), 8.99 (s,1H), 7.70-7.62 (d, J = 5.10 Hz, 1H), 7.12-7.33 (dd, J = 7.47 Hz, 1.50Hz, 1H), 7.22-7.17 (m, 1H), 7.13-7.10 (d, J = 5.07 Hz, 1H), 7.07-7.00(m, 2H), 5.85-5.81 (dd, J = 9.36 IIz, 2.75 IIz, 1II), 3.50-3.39 (m, 2H),2.80 (s, 3H). 151

HCl S LC-MS: m/z 244 (MH⁺); ¹H NMR (DMSO-d₆): δ 10.16-10.14 (d, J = 3.60Hz, 1H), 9.97 (s, 1H), 7.66- 7.64 (d, J = 5.13 Hz, 1H), 7.41-7.38 (m,1H), 7.25-7.20 (m, 1H), 7.05- 7.01 (m, 2H), 3.67-3.63 (m, 1H), 3.59-3.43(m, 3H), 2.44-2.33 (m, 2H). 152

HCl CS; FME from SFC separation of Compound 18 LC-MS (6 minute method):1.17 min, M⁺ 238 @ 1.21 min; ¹H NMR (CDCl₃): δ 7.10-7.09 (d, J = 5.1 Hz,1H), 6.91-6.89 (d, J = 5.1 Hz, 1H), 4.90-4.84 (m, 1H), 4.27-4.21 (m,1H), 3.81-3.73 (m, 1H), 3.04-2.94 (m, 1H), 2.78-2.70 (m, 1H), 2.67- 2.62(m, 2H), 2.55-2.52 (m, 4H), 1.69-1.59 (m, 4H), 1.50-1.43 (m, 2H). 153

HCl CS; SME from SFC separation of Compound 18 LC-MS (6 minute method):1.17 min, M⁺ 238 4, 1.21 min; ¹H NMR (CDCl₃): δ 7.10-7.09 (d, J = 5.1Hz, 1H), 6.91-6.89 (d, J = 5.1 Hz, 1H), 4.90-4.84 (m, 1H), 4.27-4.21 (m,1H), 3.81-3.73 (m, 1H), 3.04-2.94 (m, 1H), 2.78-2.70 (m, 1H), 2.67- 2.62(m, 2H), 2.55-2.52 (m, 4H), 1.69-1.59 (m, 4H), 1.50-1.43 (m, 2H). 154

HCl CS; FME from SFC separation of Compound 69, using isocratic 10%Methanol in CO₂ on a 4.6 × 100 mm ChiralPak AD- H from Chiral ¹H NMR(CD₃OD): δ 6.40 (d, J = 2.0 Hz, 1H), 4.86 (m, 1H), 4.28- 4.23 (m, 1H),3.90-3.84 (m, 1H), 3.45 (dd, J = 2.5, 13.0 Hz, 1H), 3.23 (dd, J = 8.5,13.0 Hz, 1H), 2.93-2.85 (m, 1H), 2.73 (s, 3H), 2.63 (dd, J = 2.0, 6.0Hz, 1H). Technologies and flow of 4 mL/min 155

HCl CS; SME from SFC separation of Compound 69, using isocratic 10%Methanol in CO₂ on a 4.6 × 100 mm ChiralPak AD- H from Chiral ¹H NMR(CD₃OD): δ 6.40 (d, J = 2.0 Hz, 1H), 4.86 (m, 1H), 4.28- 4.23 (m, 1H),3.90-3.84 (m, 1H), 3.45 (dd, J = 2.5, 13.0 Hz, 1H), 3.23 (dd, J = 8.5,13.0 Hz, 1H), 2.93-2.85 (m, 1H), 2.73 (s, 3H), 2.63 (dd, J = 2.0, 6.0Hz, 1H). Technologies and flow of 4 mL/min 156

HCl CS; FME from SFC separation of Compound 83 ¹H NMR (CD₃OD): δ 7.10(d, J = 5.0 Hz, 1H), 6.84 (d, J = 5.0 Hz, 1H), 4.82 (dd, J = 3.0, 10.5Hz, 1H), 4.33 (dt, J = 4.5, 12.5 Hz, 1H), 3.93- 3.86 (m, 1H), 3.59 (dd,J = 2.5, 12.5 Hz, 1H), 3.39-3.33 (m, 1H), 3.15- 3.08 (m, 1H), 3.01-2.80(m, 1H), 2.78 (s, 3H), 1.99-1.88 (m, 2H). 157

HCl CS; SME from SFC separation of Compound 83 ¹H NMR (CD₃OD): δ 7.10(d, J = 5.0 Hz, 1H), 6.84 (d, J = 5.0 Hz, 1H), 4.82 (dd, J = 3.0, 10.5Hz, 1H), 4.33 (dt, J = 4.5, 12.5 Hz, 1H), 3.93- 3.86 (m, 1H), 3.59 (dd,J = 2.5, 12.5 Hz, 1H), 3.39-3.33 (m, 1H), 3.15- 3.08 (m, 1H), 3.01-2.80(m, 1H), 2.78 (s, 3H), 1.99-1.88 (m, 2H). 158

HCl K LC-MS (6 minute method): 0.19 min, M⁺ 187 @ 0.38 min; ¹H NMR(CD₃OD): δ 7.28 (d, J = 5.13 Hz, 1H), 6.90 (d, J = 5.13 Hz, 1H),5.04-5.00 (m, 1H), 4.29-4.24 (m, 1H), 3.85-3.79 (m, 1H), 3.56 (dd, J =2.57, 12.8 Hz, 1H), 3.31-3.21 (m, 1H), 3.04-2.96 (m, 1H), 2.84-2.78 (m,1H). 159

HCl CS; FME from SFC separation of Compound 91 LC-MS (6 minute method):2.03 min, M⁺ 224 @ 2.13 min; ¹H NMR (CD₃OD): δ 6.65 (s, 1H), 3.97-3.89(m, 2H), 3.57-3.47 (m, 3H), 3.34 (d, J = 12.1 Hz, 1H), 2.78-2.73 (m,4H), 2.32-2.28 (m, 2H), 1.24 (t, J = 7.70 Hz, 3H). 160

HCl CS; SME from SFC separation of Compound 91 LC-MS (6 minute method):2.03 min, M⁺ 224 @ 2.13 min; ¹H NMR (CD₃OD): δ 6.65 (s, 1H), 3.97-3.89(m, 2H), 3.57-3.47 (m, 3H), 3.34 (d, J = 12.1 Hz, 1H), 2.78-2.73 (m,4H), 2.32-2.28 (m, 2H), 1.24 (t, J = 7.70 Hz, 3H). 161

HCl CS; FME from SFC separation of Compound 125 LC-MS (6 minute method):1.42 min, M⁺ 207 @ 1.41 min; ¹H NMR (CD₃OD): δ 7.61 (s, 1H), 7.16 (d, J= 4.76 Hz, 1H), 7.03 (s, 1H), 6.81 (d, J = 5.13 Hz, 1H), 5.94 (s, 1H),4.16-4.12 (m, 1H), 3.93-3.86 (m, 1H), 2.87-2.80 (m, 1H), 2.74-2.68 (m,1H). 162

HCl CS; SME from SFC separation of Compound 125 LC-MS (6 minute method):1.42 min, M⁺ 207 @ 1.41 min; ¹H NMR (CD₃OD): δ 7.61 (s, 1H), 7.16 (d, J= 4.76 Hz, 1H), 7.03 (s, 1H), 6.81 (d, J = 5.13 Hz, 1H), 5.94 (s, 1H),4.16-4.12 (m, 1H), 3.93-3.86 (m, 1H), 2.87-2.80 (m, 1H), 2.74-2.68 (m,1H). 163

HCl V LC-MS: m/z 204 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.06 (s, 3H), 7.08 (s,1H), 4.82-4.80 (d, J = 6.95 Hz, 1H), 4.15-4.11 (m, 1H), 3.80-3.77 (m,1H), 3.03-2.96 (m, 1H), 2.88-2.68 (m, 3H). 164

HCl V LC-MS: m/z 218 (MH⁺); ¹H NMR (CD₃OD): δ 6.84 (s, 1H), 4.94- 4.91(m, 1H), 4.31-4.24 (m, 1H), 3.91-3.82 (m, 1H), 3.52-3.48 (m, 1H),3.29-3.22 (m, 2H), 3.00-2.89 (m, 1H), 2.75 (s, 3H) 165

HCl V LC-MS: m/z 238 (MH⁺); ¹H NMR (CD₃OD): δ 7.45 (s, 1H), 4.97-4.94(m, 1II), 4.35-4.28 (m, 1II), 3.92- 3.83 (m, 1H), 3.56-3.51 (dd, J =13.12 Hz, 2.68 Hz, 1H), 3.23-3.02 (dd, J = 13.10 Hz, 18.16 Hz, 1H),3.07-3.04 (m, 1H), 2.92-2.86 (m, 1H). 166

HCl V LC-MS: m/z 252 (MH⁺); ¹H NMR (CDCl₃): δ 9.43 (s, 1H), 8.89 (s,1H), 5.35-5.33 (d, J = 8.46 Hz, 1H), 4.27-4.23 (m, 1H), 3.94-3.86 (m,1H), 3.55-3.52 (d, J = 9.27 Hz, 1H), 3.17-3.12 (m, 2H), 3.09-3.03 (m,1II), 2.85 (s, 3II), 2.80 (s, 1II). 167

HCl V LC-MS: m/z 188 (MH⁺); ¹H NMR (D₂O): δ 6.27-6.26 (d, J = 2.15 Hz,1H), 4.85-4.84 (m, 1H), 4.15-4.09 (m, 1H), 3.84-3.76 (m, 1H), 3.34-3.18(m, 2H), 2.82-2.72 (m, 1H), 2.64-2.50 (m, 1H). 168

HCl V LC-MS: m/z 202 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.28 (brs, 1H), 8.73(brs, 1H), 6.64-6.63 (d, J = 2.11 Hz, 1H), 4.93-4.90 (m, 1H), 4.17-4.10(m, 1H), 3.85-3.77 (m, 1H), 3.17- 3.06 (m, 1H), 2.83-2.73 (m, 3H),2.62-2.51 (m, 3H). 169

HCl CS; FME from SFC separation of Compound 139 LC-MS: m/z 184 (MH⁺); ¹HNMR (DMSO-d₆): δ 8.06 (s, 3H), 7.10 (s, 1H), 5.02-4.99 (d, J = 8.93 Hz,1H), 4.19-1.13 (m, 1H), 3.80-3.72 (m, 1H), 3.22-3.14 (m, 1H), 2.99-2.89(m, 1H), 2.65-2.60 (m, 2H), 2.05 (s, 3H). 170

HCl CS; SME from SFC separation of Compound 139 LC-MS: m/z 184 (MH⁺); ¹HNMR (DMSO-d₆): δ 8.06 (s, 3H), 7.10 (s, 1H), 5.02-4.99 (d, J = 8.93 Hz,1H), 4.19-1.13 (m, 1H), 3.80-3.72 (m, 1H), 3.22-3.14 (m, 1H), 2.99-2.89(m, 1H), 2.65-2.60 (m, 2H), 2.05 (s, 3H). 171

HCl CS; FME from SFC separation of Compound 140, using isocratic 10%Methanol: Isopropanol (1:1) w/0.1% Diethylamine in CO₂ on a 4.6 × 100 mmLux LC-MS (6 minute method): 0.46 min, M⁺ 198 @ 0.48 mm; ¹H NMR (CD₃OD):δ 6.99 (s, 1H), 5.12-5.09 (m, 1H), 4.32-4.27 (m, 1H), 3.86- 3.80 (m,1H), 3.49-3.45 (m, 1H), 3.25 (dd, J = 8.43, 12.83 Hz, 1H), 2.74 (s, 3H),2.73-2.68 (m, 1H), 2.58-2.52 (m, 1H), 2.15 (s, 3H). Cellulose-2,Phenomenex and flow of 4 mL/min 172

HCl CS; SME from SFC separation of Compound 140, using isocratic 10%Methanol: Isopropanol (1:1) w/0.1% Diethylamine in CO₂ on a 4.6 × 100 mmLux LC-MS (6 minute method): 0.46 mm, M⁺ 198 @ 0.48 mm; ¹H NMR (CD₃OD):δ 6.99 (s, 1H), 5.12-5.09 (m, 1H), 4.32-4.27 (m, 1H), 3.86- 3.80 (m,1H), 3.49-3.45 (m, 1H), 3.25 (dd, J = 8.43, 12.83 Hz, 1H), 2.74 (s, 3H),2.73-2.68 (m, 1H), 2.58-2.52 (m, 1H), 2.15 (s, 3H). Cellulose-2,Phenomenex and flow of 4 mL/min 173

HCl CS; FME from SFC separation of Compound 121, using isocratic 3%Hexane: Ethanol (1:1) in CO₂ on a 4.6 × 100 mm (S,S) WhelK0-1 fromLC-MS: m/z 216 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.25 (s, 1H), 8.67 (s, 1H),5.00-4.97 (d, J = 8.10 Hz, 1H), 4.08-4.00 (m, 1H), 3.88-3.79 (m, 1H),3.41-3.14 (m, 2H), 2.77-2.65 (m, 5H), 2.01-2.00 (d, J = 2.10 Hz, 3H).Regisand flow of 4 mL/min 174

HCl CS; SME from SFC separation of Compound 121, using isocratic 3%Hexane: Ethanol (1:1) in CO₂ on a 4.6 × 100 mm (S,S) Whelk0-1 fromLC-MS: m/z 216 (MII⁺); ¹H NMR (DMSO-d₆): δ 9.25 (s, 1H), 8.67 (s, 1H),5.00-4.97 (d, J = 8.10 Hz, 1II), 4.08-4.00 (m, 1II), 3.88-3.79 (m, 1H),3.41-3.14 (m, 2H), 2.77- 2.65 (m, 5H), 2.01-2.00 (d, J = 2.10 Hz, 3H).Regisand flow of 4 mL/min 175

HCl Q LC-MS: m/z 168 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.11 (s, 3H), 6.96 (s,1H), 3.31-3.25 (m, 1H), 3.08-3.02 (m, 1H), 2.97-2.94 (m, 1H), 2.80- 2.65(m, 2H), 2.61-2.53 (m, 1H), 2.43-2.34 (m, 1H), 2.13-2.13 (d, J = 0.84Hz, 3H). 176

HCl Q LC-MS: m/z 182 (MH⁺); ¹H NMR (CD₃OD): δ 6.89 (s, 1H), 3.33-3.32(m, 1H), 3.31-3.28 (m, 1H), 3.09- 2.97 (m, 2H), 2.93-2.83 (m, 1H),2.81-2.68 (m, 4H), 2.44-2.22 (m, 1H), 2.22 (s, 3H). 177

HCl Y LC-MS: m/z 154 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.23 (s, 3H), 7.44- 7.43(d, J = 4.50 Hz, 1H), 6.87-6.86 (d, J = 4.85 Hz, 1H), 3.51 (s, 1H), 3.05(s, 1H), 2.79-2.56 (m, 4H), 2.35-2.24 (m, 1H). 178

HCl Y LC-MS: m/z 168 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.07-9.06 (m, 2H),7.45-7.44 (d, J = 4.88 Hz, 1H), 6.88-6.86 (d, J = 4.86 Hz, 1H),3.60-3.58 (d, J = 3.39 Hz, 1H), 3.20-3.13 (m, 1H), 2.97-2.86 (m, 1H),2.81-2.60 (m, 3H), 2.57-2.53 (m, 3H), 2.43-2.31 (m, 1H). 179

HCl Y LC-MS: m/z 168 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.10 (s, 3H), 7.02 (s,1H), 3.09-3.01 (m, 2H), 2.84-2.75 (m, 2H), 2.69-2.54 (m, 3H), 2.33- 2.21(m, 1H), 2.09-2.08 (d, J = 0.93 Hz, 3H). 180

HCl Z LC-MS: m/z 236 (MH⁺); ¹H NMR (DMSO-d₆): δ 7.27-7.26 (d, J = 3.99Hz, 1H), 6.97-6.96 (d, J = 4.23 Hz, 1H), 3.62-3.57 (m, 1H), 3.34- 3.21(m, 3H), 3.10-3.02 (m, 1H), 2.91 (s, 2H), 2.68 (s, 2H), 1.77-1.72 (m,9H), 1.38 (s, 1H). 181

HCl AA LC-MS: m/z 168 (MH⁺); ¹H NMR (CDCl₃): δ 7.11-7.10 (d, J = 5.07Hz, 1H), 6.80-6.78 (d, J = 5.10 Hz, 1H), 2.99-2.89 (m, 3H), 2.70-2.60(m, 2H), 2.05-1.71 (m, 1H), 1.77- 1.59 (m, 1H), 1.44 (s, 2H). 182

HCl AA LC-MS: m/z 182 (MH⁺); ¹H NMR (CD₃OD): δ 7.26-7.24 (d, J = 5.10Hz, 1H), 6.82-6.81 (d, J = 5.10 Hz, 1H), 3.42-3.23 (m, 2H), 3.14- 3.06(m, 1H), 2.74 (s, 3H), 2.69- 2.65 (m, 2H), 2.320-2.07 (m, 1H), 2.03-1.96(m, 1H), 1.82-1.67 (m, 2H). 183

HCl AA LC-MS: m/z 236 (MH⁺); ¹H NMR (CD₃OD): δ 7.15-7.14 (d, J = 5.15Hz, 1H), 6.76-6.74 (d, J = 5.17 Hz, 1H), 4.09-4.05 (t, J = 12.90 Hz,2H), 3.59-3.55 (t, J = 12.90 Hz, 2H), 3.43-3.36 (m, 1H), 3.19-3.17 (m,1H), 3.12-3.01 (m, 1H), 2.64- 2.61 (m, 2H), 1.96-1.90 (m, 2H), 1.72-1.51(m, 6H), 1.50-1.43 (m, 2H). 184

HCl Z LC-MS: m/z 182 (MH⁺); ¹H NMR (CD₃OD): δ 6.84 (s, 1H), 3.09-2.96(m, 2H), 2.80-2.73 (m, 2H), 2.18 (s, 3H), 2.05-2.02 (m, 1H), 2.00-1.85(m, 4H). 185

HCl Z LC-MS: m/z 196 (MH⁺); ¹H NMR (CD₃OD): δ 6.74 (s, 1H), 2.95 (d, J =11.86 Hz, 1H), 2.83-2.76 (m, 1H), 2.74-2.68 (m, 2H), 2.65-2.60 (m, 1H),2.52-2.45 (dd, J = 12.55 Hz, 6.96 Hz, 1H), 2.41 (s, 1H), 2.30- 2.26 (d,J = 13.27 Hz, 1H), 2.21- 2.20 (m, 1H), 2.182-2.179 (m, 3H), 1.89-1.81(m, 2H), 1.67-1.58 (m, 1H). 186

HCl Z LC-MS: m/z 250 (MH⁺); ¹H NMR (CD₃OD): δ 6.72 (s, 1H), 3.01-2.97(d, J = 10.96 Hz, 1H), 2.82-2.62 (m, 3H), 2.52-2.45 (m, 3H), 2.30-2.20(m, 2H), 2.17 (s, 3H), 1.91-1.81 (m, 2H), 1.72-1.49 (m, 8H). 187

HCl B LC-MS: m/z 195 (MH⁺); ¹H NMR (CD₃OD): δ 7.42-7.40 (d, J = 5.1 Hz,1H), 6.90-6.89 (d, J = 5.1 Hz, 1H), 4.05-3.95 (m, 2H), 3.71- 3.70 (m,1H), 3.67-3.55 (m, 2H), 3.39-3.35 (m, 1H), 2.80-2.79 (m, 2H), 2.55-2.48(m, 1H), 2.39-2.84 (m, 1H). 188

HCl B LC-MS: m/z 209 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.26-9.23 (d, J = 8.75Hz, 1H), 8.41-8.32 (m, 1H), 7.49-7.44 (dd, J = 8.75 Hz, 5.10 Hz, 1H),6.91-6.88 (m, 1H), 3.94-3.90 (m, 2H), 3.94-3.92 (m, 1H), 3.19- 3.15 (m,2H), 3.07-2.99 (m, 1H), 2.73-2.61 (m, 2H), 2.01-1.80 (m, 3H), 1.71-1.67(m, 1H). 189

HCl B LC-MS: m/z 209 (MH⁺); ¹H NMR (D₂O): δ 6.94 (s, 1H), 3.99-3.92 (m,1H), 3.88-3.79 (m, 1H), 3.63-3.58 (m, 1H), 3.55-3.38 (m, 2H), 3.30- 3.26(m, 1H), 2.57-2.44 (m, 2H), 2.38-2.20 (m, 2H), 1.98 (s, 3H). 190

HCl B LC-MS: m/z 223 (MII⁺); ¹II NMR (D₂O): δ 6.89 (s, 1H), 3.96-3.92(m, 1H), 3.87-3.83 (m, 1H), 3.44- 3.39 (d, J = 13.56 Hz, 1H), 3.24- 3.20(d, J = 12.30 Hz, 1H), 3.07- 3.03 (d, J = 13.44 Hz, 1H), 2.89- 2.81 (m,1H), 2.48-2.47 (m, 2H), 1.96 (s, 3H), 1.90-1.78 (m, 3H), 1.72-1.67 (m,1H). 191

HCl BB LC-MS: m/z 224 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.22- 8.16 (d, J =13.20 Hz, 3H), 4.90- 4.86 (t, J = 12.15 Hz, 1H), 4.01- 3.94 (m, 1H),3.82-3.75 (m, 1H), 3.05 (s, 2H), 2.72-2.66 (m, 4H), 2.41-2.32 (m, 2II),1.86-1.83 (m, 2H), 1.71-1.53 (m, 2H). 192

HCl BB LC-MS: m/z 238 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.39- 9.36 (d, J =11.15 Hz, 1H), 8.70- 8.64 (m, 1H), 5.01-4.98 (m, 1H), 4.03-3.95 (m, 1H),3.83-3.76 (m, 2H), 3.17-3.02 (m, 2H), 2.79-2.57 (m, 7H), 2.50-2.42 (m,2H), 1.85- 1.82 (m, 2H), 1.70-1.51 (m, 2H). 193

HCl BB LC-MS: m/z 210 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.23 (s, 3H), 4.91-4.88(d, J = 7.80 Hz, 1H), 4.10-4.03 (m, 1H), 3.79-3.71 (m, 1H), 3.15-3.10(m, 1H), 3.01- 2.92 (m, 1H), 2.88-2.70 (m, 4H), 2.62-2.58 (m, 2H),2.39-2.31 (m, 2H). 194

HCl BB LC-MS: m/z 224 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.40 (s, 1H), 8.75 (s,1H), 5.02-4.99 (d, J = 9.05 Hz, 1H), 4.10-4.03 (m, 1H), 3.81-3.73 (m,1H), 3.24-3.01 (m, 2H), 2.86-2.71 (m, 4H), 2.68-2.50 (m, 5H), 2.42-2.35(m, 2H). 195

HCl BB LC-MS: m/z 238 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.09 (s, 3H), 4.88-4.85(d, J = 9.81 Hz, 1H), 3.97-3.78 (m, 2H), 3.55 (s, 2H), 3.12-3.06 (m,1H), 2.91-2.70 (m, 1H), 2.68-2.56 (m, 4H), 1.91-1.73 (m, 2H), 1.56-1.47(m, 4H). 196

HCl BB LC-MS: m/z 252 (MH⁺); ¹H NMR (D₂O): δ 4.91-4.89 (d, J = 7.82 Hz,1H), 3.88-3.87 (d, J = 4.74 Hz, 2H), 3.74-3.70 (m, 1H), 3.28-3.21 (m,1H), 3.13-3.08 (m, 1H), 2.63- 2.52 (m, 7H), 2.33 (s, 2H), 1.68 (s, 2H),1.43 (s, 4H). 197

HCl BB LC-MS: m/z 224 (MH⁺); ¹H NMR (D₂O): δ 5.02-5.00 (d, J = 5.72 Hz,1H), 4.13-4.06 (m, 1H), 3.77- 3.69 (m, 1H), 3.36-3.30 (m, 1H), 3.19-3.12(m, 1H), 2.65-2.42 (m, 3H), 2.36-1.68 (m, 3H), 1.66 (s, 4H). 199

HCl BB LC-MS: m/z 210 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.14 (s, 3H), 4.98-4.95(d, J = 8.71 Hz, 1H), 4.15-4.08 (m, 1H), 3.77-3.69 (m, 1H), 3.16-3.12(m, 1H), 3.03-2.93 (m, 1H), 2.84-2.79 (m, 2H), 2.67- 2.52 (m, 4H),2.42-2.33 (m, 2H). 200

HCl BB LC-MS: m/z 224 (MII⁺); ¹II NMR (DMSO-d₆): δ 9.13 (s, 1H),8.74-8.72 (d, J = 6.00 Hz, 1H), 5.09-5.05 (d, J = 9.20 Hz, 1II),4.15-4.03 (m, 4H), 3.79-3.70 (m, 1H), 3.39-3.10 (m, 2H), 2.84-2.79 (m,2H), 2.60-2.57 (t, J = 2.57 Hz, 4H), 2.42-2.33 (m, 2H). 201

HCl BB LC-MS: m/z 238 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.30 (s, 3H), 4.96-4.93(d, J = 7.92 Hz, 1H), 4.16-4.09 (m, 1H), 3.78-3.70 (m, 1H), 3.10-3.08(m, 1H), 3.00-2.91 (m, 1H), 2.76-2.69(m, 2H), 2.60- 2.52 (m, 2H),2.47-2.42 (m, 2H), 1.83-1.74 (m, 2II), 1.67-1.47 (m, 4H). 202

HCl CC LC-MS: m/z 210 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.82-9.80 (d, J = 4.11Hz, 1H), 8.86 (s, 1H), 7.51- 7.49 (d, J = 5.04 Hz, 1H), 6.96-6.74 (d, J= 5.04 Hz, 1H), 5.03-5.00 (d, J = 7.17 Hz, 1H), 4.19-4.12 (m, 1H),3.79-3.71 (m, 2H), 3.13 (s, 2H), 2.86-2.76 (m, 1H), 2.67-2.61 (m, 1H),2.26-2.22 (m, 1H), 2.04-1.87 (m, 3H). 203

HCl CC LC-MS: m/z 210 (MH⁺); ¹H NMR (DMSO-d₆): δ 10.19 (s, 1H), 8.90(brs, 1H), 7.51-7.49 (dd, J = 5.01 Hz, 0.69 Hz, 1H), 6.94-6.93 (d, J =5.01 Hz, 1H), 5.22-5.21 (d, J = 1.83 Hz, 1H), 4.25-4.20 (dd, J = 11.34Hz, 5.31 Hz, 1H), 3.95(s, 1H), 3.75-3.66 (td, J = 11.34 Hz, 3.60 Hz,1H), 3.19-3.04 (m, 2H), 2.86-2.74 (m, 1H), 2.64-2.59 (m, 1H), 1.90-1.66(m, 4H). 204

HCl CC LC-MS: m/z 210 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.82 (s, 1H), 8.87 (s,1H), 4.51-7.49 (d, J = 5.01 Hz, 1H), 6.96-6.94 (d, J = 5.04 Hz, 1H),5.03-5.01 (d, J = 7.32 Hz, 1H), 4.19-4.12 (m, 1H), 3.79-3.70 (m, 2H),3.13 (s, 2H), 2.86-2.76 (m, 1H), 2.67-2.61 (m, 1H), 2.26-2.22 (m, 1H),2.04-1.87 (m, 3H). 205

HCl CC LC-MS: m/z 210 (MH⁺); ¹H NMR (DMSO-d₆): δ 10.23 (s, 1H), 8.90 (s,1H), 7.51-7.49 (d, J = 5.78 Hz, 1H), 6.94-6.92 (s, J = 5.16 Hz, 1H),5.22 (s, 1H), 4.25-4.19 (dd, J = 11.24 Hz, 5.45 Hz, 1H), 3.94 (s, 1H),3.74-3.66 (td, J = 11.31 Hz, 3.57 Hz, 1H), 3.19-3.08 (m, 2H), 2.80-2.75(m, 1H), 2.64-2.58 (m, 1H), 1.91-1.63 (m, 4H). 206

IICl N LC-MS: m/z 198 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.02-9.00 (d, J = 5.10Hz, 1H), 8.14 (s, 1H), 7.43- 7.41 (d, J = 5.10 Hz, 1H), 7.04-7.02 (d, J= 5.12 Hz, 1H), 4.82-4.81 (d, J = 2.15 Hz, 1H), 4.22-4.15 (m, 1H),3.79-3.68 (m, 2H), 2.91-2.77 (m, 2H), 2.40-2.37 (m, 3H), 1.39-1.37 (d, J= 6.96 Hz, 3H). 207

HCl N LC-MS: m/z 184 (MH⁺); ¹H NMR (DMSO-d₆): δ 7.90 (s, 3H), 7.41-7.39(d, J = 5.19 Hz, 1II), 7.00-6.98 (d, J = 5.25 Hz, 1H), 4.72-4.71 (d, J =2.13 Hz, 1H), 4.70-4.12 (m, 1H), 3.77-3.66 (m, 2H), 3.41-3.34 (m, 2H),1.36-1.34 (d, J = 6.72 Hz, 3H). 208

HCl N LC-MS: m/z 184 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.38 (s, 3H), 7.43- 7.39(d, J = 5.19 Hz, 1H), 6.70-6.98 (d, J = 5.22 Hz, 1H), 4.98(s, 1H),4.97-4.22 (m, 1H), 3.82-3.81 (m, 1H), 3.71-3.62 (td, J = 11.13 Hz, J =3.53 Hz, 1H), 2.97-2.50 (m, 1H), 2.50-2.49 (m, 1H), 0.91-0.88 (d, J =6.72 Hz, 3H). 209

HCl N LC-MS: m/z 198 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.24-9.14 (m, 2H),7.42-7.40 (d, J = 5.17 Hz, 1H), 6.94-6.92 (d, J = 5.42 Hz, 1H),5.17-5.16 (d, J = 1.80 Hz, 1H), 4.27- 4.22 (m, 1H), 3.80 (s, 1H), 3.73-3.65 (m, 1H), 2.98-2.88 (m, 1H), 2.77-2.72 (m, 1H), 2.59 (s, 3H),0.93-0.91 (d, J = 6.62 Hz, 3H). 210

HCl N LC-MS: m/z 198 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.91 (s, 1H), 8.08 (s,1H), 7.43-7.41 (d, J = 5.22 Hz, 1H), 7.04-7.02 (d, J = 5.22 Hz, 1H),4.81-4.80 (m, 1H), 4.22-4.16 (m, 1H), 3.79-3.67 (m, 2H), 2.97- 2.77 (m,2H), 2.41-2.37 (t, J = 5.42 Hz, 3H), 1.39-1.37 (d, J = 6.75 Hz, 3H). 211

HCl N LC-MS: m/z 198 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.20-9.10 (m, 2H),7.42-7.40 (d, J = 5.10 Hz, 1H), 6.94-6.72 (d, J = 5.16 Hz, 1H), 5.15 (s,1H), 4.27-4.22 (m, 1H), 3.79- 3.65 (m, 2H), 3.74-3.65 (td, J = 11.18 Hz,3.42 Hz, 2H), 2.98-2.88 (m, 1H), 2.77-2.72 (m, 1H), 2.60 (s, 3H),0.92-0.90 (d, J = 6.66 Hz, 3H). 212

HCl DD LC-MS: m/z 184 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.03 (s, 3H), 7.52-7.50 (dd, J = 0.58 Hz, J = 5.03 Hz, 1H), 6.96-6.94 (d, J = 5.04 Hz, 1H),4.83-4.82 (d, J = 5.48 Hz, 1H), 4.17-4.10 (m, 1H), 3.77-3.69 (m, 1H),3.47 (s, 1H), 2.80-2.61 (m, 2H), 1.43-1.40 (d, J = 6.63 Hz, 3H). 213

HCl DD LC-MS: m/z 184 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.42 (s, 3H), 7.51-7.49(dd, J = 5.11 Hz, J = 0.62 Hz, 1H), 6.94-6.93 (d, J = 5.12 Hz, 1H),5.14-5.13 (d, J = 1.50 Hz, 1H), 4.25-4.19 (m, 1H), 3.71-3.62 (td, J =11.12 Hz, 3.64 Hz, 1H), 3.54 (s, 1H), 2.84-2.72 (m, 1H), 2.63-2.57 (m,1H), 1.01-0.98 (d, J = 6.95 Hz, 3H). 214

HCl DD LC-MS: m/z 184 (MH⁺); ¹H NMR (DMSO-d₆): δ 7.87 (s, 3H), 7.53-7.51(d, J = 4.65 Hz, 1H), 6.97-6.95 (d, J = 5.22 Hz, 1H), 4.82- 4.80 (d, J =5.07 Hz, 1H), 4.18-4.14 (m, 1H), 3.78-3.69 (m, 1H), 3.52- 3.44 (m, 1H),2.78-2.62 (m, 2H), 1.40-1.38 (d, J = 6.57 Hz, 3H). 215

HCl DD LC-MS: m/z 184 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.32 (s, 3H), 7.51-7.49(dd, J = 5.01 Hz, J = 0.57 Hz, 1H), 6.95-6.93 (d, J = 5.01 Hz, 1H),5.11-5.10 (d, J = 1.65 Hz, 1H), 4.25-4.20 (dd, J = 11.34 Hz, 4.98 Hz,1H), 3.72-3.63 (td, J = 11.27 Hz, 3.51 Hz, 1H), 3.57 (s, 1H), 2.84-2.72(m, 1H), 2.63-2.58 (m, 1H), 1.01-0.98 (d, J = 6.75 Hz, 3H). 216

HCl DD LC-MS: m/z 198 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.09 (s, 1H), 8.35-8.32(m, 1H), 7.53-7.52 (d, J = 5.12 Hz, 1H), 6.97-6.95 (d, J = 4.80 Hz, 1H),4.93 (d, J = 1.7 Hz, 1H), 4.19-4.12 (m, 1H), 3.80-3.72 (m, 1H),3.54-3.51 (m, 1H), 2.77-2.64 (m, 2H), 2.50-2.45 (m, 3H), 1.46- 1.43 (d,J = 6.64 Hz, 3H). 217

HCl DD LC-MS: m/z 198 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.42-9.17 (m, 2H),7.50-7.49 (d, J = 4.85 Hz, 1H), 6.94-6.92 (d, J = 5.18 Hz, 1H),5.33-5.33 (d, J = 1.27 Hz, 1H), 4.24-4.19 (dd, J = 11.28 Hz, 5.37 Hz,1H), 3.73-3.64 (td, J = 11.31 Hz, 5.37 Hz, 1H), 3.53(s, 1H), 2.84- 2.72(m, 1H), 2.63-2.62 (m, 1H), 2.60 (s, 3H), 1.02-1.00 (d, J = 6.9 Hz, 3H).218

HCl DD LC-MS: m/z 198 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.07-9.06 (d, J = 5.45Hz, 1H), 8.31 (s, 1H), 7.53- 7.52 (d, J = 5.01 Hz, 1H), 6.97-6.95 (d, J= 5.04 Hz, 1H), 4.94-4.92 (s, J = 5.28 Hz, 1H), 4.19-4.13 (m, 1H),3.80-3.72 (m, 1H), 3.42-3.49 (m, 1H), 2.82-2.64 (m, 2H), 2.50-2.45 (m,3H), 1.46-1.43 (d, J = 6.63 Hz, 3H). 219

HCl DD LC-MS: m/z 198 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.39-9.38 (d, J = 1.17Hz, 1H), 9.16-9.14 (d, J = 4.92 Hz, 1H), 7.51-7.49 (dd, J = 4.95 Hz,0.42 Hz, 1H), 6.94-6.93 (d, J = 5.01 Hz, 1H), 5.33-5.32 (d, J = 1.49 Hz,1H), 4.24-4.19 (dd, J = 11.33 Hz, 5.21 Hz, 1H), 3.73-3.64 (td, J = 11.31Hz, 3.57 Hz, 1H), 3.55-3.53 (m, 1H), 2.84-2.72 (m, 1H), 2.63- 2.58 (m,4H), 1.10-0.99 (d, J = 6.72 Hz, 3H). 220

HCl CS; FME from SFC separation of Compound 29, using isocratic 10%Hexane: Ethanol (1:1) in CO₂ on a 4.6 × ¹H NMR (DMSO-d₆): δ 8.14 (br s,3H), 7.00 (s, 1H), 4.97-4.90 (m, 1H), 4.02-3.94 (m, 1H), 3.85-3.78 (m,1H), 3.11-3.08 (t, J = 10.66 Hz, 2H), 2.88-2.73 (m, 2H), 2.13-2.12 (d, J= 0.8 Hz, 3H). 100 mm LUX Cellulose 2 from Phenomenex and flow of 4mL/min 221

IICl CS; SME from SFC separation of Compound 29, using isocratic 10%Hexane: Ethanol (1:1) in CO₂ on a 4.6 × ¹H NMR (DMSO-d₆): δ 8.14 (br s,3H), 7.00 (s, 1H), 4.97-4.90 (m, 1H), 4.02-3.94 (m, 1H), 3.85-3.78 (m,1H), 3.11-3.08 (t, J = 10.66 Hz, 2II), 2.88-2.73 (m, 2II), 2.13-2.12 (d,J = 0.8 Hz, 3H). 100 mm LUX Cellulose 2 from Phenomenex and flow of 4mL/min 222

HCl K LC-MS (6 minute method): 0.67 min, M⁺ 201 @ 0.63 min; ¹H NMR(CD₃OD): δ 6.90 (s, 1H), 5.05-5.02 (m, 1H), 4.17-4.12 (m, 1H), 3.86-3.81 (m, 1H), 3.46-3.42 (m, 1H), 3.33-3.28 (m, 1H), 2.93-2.81 (m, 1H),2.19 (s, 3H). 223

HCl K LC-MS (6 minute method): 0.67 min, M⁺ 201 @ 0.63 mm; ¹H NMR(CD₃OD): δ 6.90 (s, 1H), 5.05-5.02 (m, 1H), 4.17-4.12 (m, 1H), 3.86-3.81 (m, 1H), 3.46-3.42 (m, 1H), 3.33-3.28 (m, 1H), 2.93-2.81 (m, 1H),2.19 (s, 3H). 224

HCl K LC-MS (6 minute method): 0.70 min, M⁺ 201 @ 0.73 mm; ¹H NMR(CD₃OD): δ 6.99 (s, 1H), 5.10 (d, J = 8.07 Hz, 1H), 4.32-4.27 (m, 1H),3.86-3.80 (m, 1H), 3.48-3.44 (m, 1H), 3.27-3.24 (m, 1H), 2.76-2.68 (m,1H), 2.57-2.52 (m, 1H), 2.14 (s, 3H). 225

HCl K LC-MS (6 minute method): 0.70 min, M⁺ 201 @ 0.73 mm; ¹H NMR(CD₃OD): δ 6.99 (s, 1H), 5.10 (d, J = 8.07 Hz, 1H), 4.32-4.27 (m, 1H),3.86-3.80 (m, 1H), 3.48-3.44 (m, 1H), 3.27-3.24 (m, 1H), 2.76-2.68 (m,1H), 2.57-2.52 (m, 1H), 2.14 (s, 3H). 226

HCl K LC-MS (6 minute method): 0.17- 0.36 min, M⁺ 187 @ 0.35 min; ¹H NMR(CD₃OD): δ 7.37 (d, J = 2.93 Hz, 1H), 6.90 (d, J = 2.93 Hz, 1H), 5.16(d, J = 7.33 Hz, 1H), 4.28-4.24 (m, 1H), 3.85-3.80 (m, 1H), 3.50 (d, J =12.8 Hz, 1H), 3.3-3.25 (m, 1H), 2.89-2.84 (m, 1H), 2.71-2.67 (m, 1H).227

HCl K LC-MS (6 minute method): 0.17- 0.36 min, M⁺ 187 @ 0.35 min; ¹H NMR(CD₃OD): δ 7.37 (d, J = 2.93 Hz, 1H), 6.90 (d, J = 2.93 Hz, 1H), 5.16(d, J = 7.33 Hz, 1H), 4.28-4.24 (m, 1H), 3.85-3.80 (m, 1H), 3.50 (d, J =12.8 Hz, 1H), 3.3-3.25 (m, 1H), 2.89-2.84 (m, 1H), 2.71-2.67 (m, 1H).228

HCl EE LC-MS: m/z 207 (MH⁺); ¹H NMR (CD₃OD): δ 8.20-8.19 (d, J = 2.61Hz, 1H), 7.30-7.29 (d, J = 5.25 Hz, 1H), 6.79-6.74 (m, 2H), 6.08 (s,1H), 4.21-4.15 (m, 1H), 4.04-3.96 (m, 1H), 3.11-3.02 (m, 1H), 2.98- 2.89(m, 1H). 229

HCl EE LC-MS: m/z 207 (MH⁺); ¹H NMR (D₂O): δ 7.73 (s, 1H), 7.23-7.22 (d,J = 3.72 Hz, 1H), 6.82 (s, 1H), 6.41 (s, 1H), 6.02 (s, 1H), 4.00-3.95(m, 1H), 3.85-3.81 (m, 1H), 2.77- 2.62 (m, 2H). 230

HCl EE LC-MS: m/z 221 (MH⁺); ¹H NMR (CD₃OD): δ 7.31-7.29 (d, J = 5.19Hz, 1H), 6.81-6.79 (d, J = 5.22 Hz, 1H), 6.56 (s, 1H), 6.09 (s, 1H),4.21-4.14 (m, 1H), 4.03-3.95 (m, 1H), 3.09-2.90 (m, 2H), 2.46 (s, 3H).231

HCl EE LC-MS: m/z 221 (MH⁺); ¹H NMR (CD₃OD): δ 7.41-7.39 (dd, J = 5.09Hz, 0.71 Hz, 1H), 6.95-6.93 (d, J = 5.07 Hz, 1H), 6.63 (s, 1H), 6.16 (s,1H), 4.21-4.14 (m, 1H), 4.02- 3.94 (m, 1H), 2.97-2.87 (m, 1H), 2.84-2.75(m, 1H), 1.19 (s, 3H). 232

HCl EE LC-MS: m/z 221 (MH⁺);¹H NMR (DMSO-d₆): δ 9.71-9.66 (d, J = 15.52Hz, 1H), 7.36-7.33 (m, 2H), 6.62-6.61 (d, J = 5.19 Hz, 1H), 5.98 (s,1H), 5.91-5.90 (d, J = 1.77 Hz, 1H), 3.93-3.79 (m, 2H), 3.76 (s, 3H),2.89-2.86 (t, J = 5.27 Hz, 2H). 233

HCl EE LC-MS: m/z 221 (MH⁺); ¹H NMR (CDCl₃): δ 12.01 (s, 1H), 7.85- 7.84(d, J = 2.40 Hz, 1H), 7.30-7.28 (m, 1H), 6.91-6.87 (d, J = 5.07 Hz, 1H),6.50-6.49 (d, J = 2.34 Hz, 1H), 6.08 (s, 1H), 4.20 (s, 3H), 4.07-4.00(m, 1H), 3.96-3.88 (m, 1H), 2.91- 2.88 (m, 2H). 234

HCl EE LC-MS: m/z 221 (MH⁺); ¹H NMR (CD₃OD): δ 8.67 (s, 1H), 7.27-7.25(d, J = 5.25 Hz, 1H), 6.57-6.56 (d, J = 5.28 Hz, 1H), 5.97-5.96 (m, 1H),4.25-4.19 (m, 1H), 4.01-3.93 (m, 1H), 3.17-3.07 (m, 1H), 2.92-2.86 (m,1H), 2.29 (s, 3H). 235

HCl EE LC-MS: m/z 221 (MH⁺); ¹H NMR (CD₃OD): δ 8.17 (s, 1H), 7.33- 7.31(dd, J = 5.07 Hz, 0.75 Hz, 1H), 6.92-6.70 (d, J = 5.07 Hz, 1H), 6.02 (s,1H), 4.27-4.20 (m, 1H), 3.97- 3.90 (m, 1H), 3.00-2.92 (m, 1H), 2.78-2.71(m, 1H), 2.24 (s, 3H). 236

HCl EE LC-MS: m/z 221 (MH⁺); ¹H NMR (CD₃OD): δ 7.16-7.14 (d, J = 5.19Hz, 1H), 6.68-6.67 (d, J = 0.48 Hz, 1H), 6.64-6.62 (d, J = 5.16 Hz, 1H),5.71 (s, 1H), 4.11-4.04 (m, 1H), 3.91-3.84 (m, 1H), 2.98-2.82 (m, 2H),2.33 (s, 3H). 237

HCl EE LC-MS: m/z 221 (MH⁺); ¹H NMR (CD₃OD): δ 7.27-7.25 (dd, J = 5.07Hz, 0.75 Hz, 1H), 6.87-6.85 (d, J = 5.04 Hz, 1H), 6.84 (s, 1H), 5.82 (s,1H), 4.17-4.10 (m, 1H), 3.92- 3.86 (m, 1H), 2.89-2.81 (m, 1H), 2.76-2.69(m, 1H), 2.34 (s, 3H). 238

HCl EE LC-MS: m/z 221 (MH⁺); ¹H NMR (CD₃OD): δ 8.95 (s, 1H), 7.35- 7.33(d, J = 5.25 Hz, 1H), 7.29 (s, 1H), 6.75-6.73 (d, J = 5.25 Hz, 1H), 6.10(s, 1H), 4.02-3.97 (m, 2H), 3.89 (s, 3H), 3.00-2.97 (m, 2H). 239

HCl EE LC-MS: m/z 221 (MH⁺); ¹H NMR (CD₃OD): δ 8.96 (s, 1II), 7.48- 7.47(d, J = 1.11 Hz, 1H), 7.45-7.44 (dd, J = 5.07 Hz, 0.69 Hz, 1H), 6.98 (d,J = 1.1 Hz, 1H), 6.25 (s, 1H), 4.09-3.92 (m, 2H), 3.88-3.87 (d, J = 0.45Hz, 3H), 2.89-2.84 (m, 2H). 240

HCl B ¹H NMR (CD₃OD): δ 7.36 (d, J = 1.5 Hz, 1H), 6.91 (d, J = 1.5 Hz,1H), 5.13 (d, J = 2.0 Hz, 1H), 4.26 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H),3.82 (dt, J = 3.0, 1.0 Hz, 1H), 3.46 (dd, J = 3.0, 0.7 Hz, 1H), 3.25(dd, J = 3.0, 2.0 Hz, 1H), 3.12 (q, J = 1.7 Hz, 2H) 2.91-2.83 (m, 1H),2.71-2.65 (m, 1H), 1.32 (t, J = 1.7 Hz, 3H). 241

HCl CS; FME from SFC separation of Compound 240, using isocratic 8%Hexane: Ethanol (1:1) in CO₂ on a 4.6 × 100 mm LUX Cellulose 2 from ¹HNMR (CD₃OD): δ 7.36 (d, J = 1.5 Hz, 1H), 6.91 (d, J = 1.5 Hz, 1H), 5.13(d, J = 2.0 Hz, 1H), 4.26 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.82 (dt, J =3.0, 1.0 Hz, 1H), 3.46 (dd, J = 3.0, 0.7 Hz, 1H), 3.25 (dd, J = 3.0, 2.0Hz, 1H), 3.12 (q, J = 1.7 Hz, 2H) 2.91-2.83 (m, 1H), 2.71-2.65 (m, 1H),1.32 (t, J = 1.7 Hz, 3H). Phenomenex and flow of 4 mL/min 242

IICl CS; SME from SFC separation of Compound 240, using isocratic 8%Hexane: Ethanol (1:1) in CO₂ on a 4.6 × 100 mm LUX Cellulose 2 from ¹HNMR (CD₃OD): δ 7.36 (d, J = 1.5 Hz, 1H), 6.91 (d, J = 1.5 Hz, 1H), 5.13(d, J = 2.0 Hz, 1H), 4.26 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.82 (dt, J =3.0, 1.0 Hz, 1H), 3.46 (dd, J = 3.0, 0.7 Hz, 1H), 3.25 (dd, J = 3.0, 2.0IIz, 1II), 3.12 (q, J = 1.7 IIz, 2H) 2.91-2.83 (m, 1H), 2.71-2.65 (m,1H), 1.32 (t, J = 1.7 Hz, 3H). Phenomenex and flow of 4 mL/min 243

HCl B ¹H NMR (CD₃OD): δ 7.37 (d, J = 1.2 Hz, 1H), 6.91 (d, J = 1.2 Hz,1H), 5.12 (apd, J = 1.8 Hz, 1H), 4.26 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H),3.82 (ddd, J = 3.0, 2.5, 1.0 Hz, 1H), 3.49-3.40 (m, 2H), 3.28-3.21 (m,1H), 2.92-2.83 (m, 1H), 2.72-2.67 (m, 1H), 1.35 (dd, J = 2.3, 1.6 Hz,6H). 244

HCl CS; FME from SFC separation of Compound 243, using isocratic 8%Hexane: Ethanol (1:1) in CO₂ on a 4.6 × 100 mm LUX Cellulose 2 from ¹HNMR (CD₃OD): δ 7.37 (d, J = 1.2 Hz, 1H), 6.91 (d, J = 1.2 Hz, 1H), 5.12(apd, J = 1.8 Hz, 1H), 4.26 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.82 (ddd,J = 3.0, 2.5, 1.0 Hz, 1H), 3.49-3.40 (m, 2H), 3.28-3.21 (m, 1H),2.92-2.83 (m, 1H), 2.72-2.67 (m, 1H), 1.35 (dd, J = 2.3, 1.6 Hz, 6H).Phenomenex and flow of 4 mL/min 245

IICl CS; SME from SFC separation of Compound 243, using isocratic 8%Hexane: Ethanol (1:1) in CO₂ on a 4.6 × 100 mm LUX Cellulose 2 from ¹HNMR (CD₃OD): δ 7.37 (d, J = 1.2 Hz, 1H), 6.91 (d, J = 1.2 Hz, 1H), 5.12(apd, J = 1.8 Hz, 1H), 4.26 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.82 (ddd,J = 3.0, 2.5, 1.0 Hz, 1H), 3.49-3.40 (m, 2H), 3.28-3.21 (m, 1II),2.92-2.83 (m, 1II), 2.72-2.67 (m, 1H), 1.35 (dd, J = 2.3, 1.6 Hz, 6H).Phenomenex and flow of 4 mL/min 246

HCl B ¹H NMR (CD₃OD): δ 7.36 (d, J = 1.3 Hz, 1H), 6.91 (d, J = 1.3 Hz,1H), 5.24 (apd, J = 2.5 Hz, 1H), 4.29-4.25 (m, 1H), 3.85 (dt, J = 2.5,1.0 Hz, 1H), 3.81-3.67 (m, 1H), 3.66-3.63 (m, 2H), 3.50 (dd, J = 3.0,2.5 Hz, 1H), 3.31-3.12 (m, 2H), 2.91-2.83 (m, 1H), 2.73-2.68 (m, 1H),2.19-2.00 (m, 4H). 247

HCl T LC-MS: m/z 246 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.29 (s, 1H), 8.92 (s,1H), 7.66-7.64 (d, J = 5.10 Hz, 1H), 7.10-7.37 (dd, J = 7.47 Hz, 1.50Hz, 1H), 7.27-7.21 (m, 1H), 7.13-7.11 (d, J = 5.07 Hz, 1H), 7.07-7.00(m, 2H), 5.88-5.84 (dd, J = 9.36 Hz, 2.75 Hz, 1H), 3.50-3.39 (m, 2H),3.07-3.02 (m, 2H), 1.27- 1.22 (t, J = 7.23 Hz, 3H). 248

HCl U LC-MS: m/z 218 (MH⁺); ¹H NMR (DMSO-d₆): δ8.40 (s, 3H), 7.71- 7.64(m, 2H), 7.59-7.57 (d, J = 5.10 Hz, 1H), 7.26-7.21 (m, 1H), 7.08- 7.03(m, 2H), 5.87-5.82 (dd, J = 8.90 Hz, 3.23 Hz, 1H), 3.31-3.25 (m, 2H).249

HCl U LC-MS: m/z 232 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.36 (s, 1H), 9.09 (s,1H), 7.72-7.70 (d, J = 5.10 Hz, 1H), 7.67-7.75 (d, J = 6.27 Hz, 1H),7.59-7.57 (d, J = 5.13 Hz, 1H), 7.27-7.21 (m, 1H), 7.09-7.03 (m, 2H),6.01-5.96 (dd, J = 8.18 Hz, J = 4.28 Hz, 1H), 3.37 (s, 2H), 2.65 (s,3H). 250

HCl U LC-MS: m/z 246 (MH⁺); ¹H NMR (DMSO-d₆ + D₂O): δ 7.69-7.62 (m, 2H),7.56-7.55 (d, J = 5.07 Hz, 1H), 7.26-7.21 (m, 1H), 7.09-7.03 (m, 2H),5.93-5.88 (t, J = 12.3 Hz, 1H), 3.44-3.33 (m, 2H), 3.10-3.03 (m, 2H),1.24-1.19 (t, J = 7.22 Hz, 3H). 251

HCl CS; FME from SFC separation of Compound 144, using isocratic 5%isopropyl amine in Methanol:Hexane (1:1) w/ 3% isopropanol in ¹H NMR(CD₃OD): δ 7.21 (d, J = 1.5 Hz, 1H), 6.92 (d, J = 1.5 Hz, 1H), 3.36 (dd,J = 3.0, 1.0 Hz, 1H), 3.14 (m, 1H), 3.09 (dd, J = 3.0, 2.5 Hz, 1H), 2.80(apt, J = 1.5 Hz, 2H), 2.75 (s, 3H), 2.03-1.95 (m, 2H), 1.88-1.81 (m,1H), 1.72-1.65 (m, 1H). CO₂ on a 4.6 × 100 mm RegisPack from Regis andflow of 4 mL/min 252

HCl CS; SME from SFC separation of Compound 144, using isocratic 5%isopropyl amine in Methanol:Hexane (1:1) w/ 3% isopropanol in ¹H NMR(CD₃OD): δ 7.21 (d, J = 1.5 Hz, 1H), 6.92 (d, J = 1.5 Hz, 1H), 3.36 (dd,J = 3.0, 1.0 Hz, 1H), 3.14 (m, 1H), 3.09 (dd, J = 3.0, 2.5 Hz, 1H), 2.80(apt, J = 1.5 Hz, 2H), 2.75 (s, 3H), 2.03-1.95 (m, 2H), 1.88-1.81 (m,1H), 1.72-1.65 (m, 1H). CO₂ on a 4.6 × 100 mm RegisPack from Regis andflow of 4 mL/min 253

HCl A ¹H NMR (CD₃OD): δ 9.85 (d, J = 0.5 Hz, 1H), 7.88 (d, J = 0.5 Hz,1H), 7.28 (d, J = 1.3, 1H), 6.73 (d, J = 1.3 H, 1H), 6.09 (s, 1H), 4.12-3.95 (m, 2H), 2.99 (ddt, J = 11.0, 4.0, 1.5 Hz, 2H). 254

HCl A ¹H NMR (CD₃OD): δ 9.52 (d, J = 0.5 Hz, 1H), 7.82 (d, J = 0.5 Hz,1H), 7.34 (d, J = 1.3, 1H), 6.91 (d, J = 1.3 II, 1II), 6.17 (s, 1II),4.15 (dt, J = 2.5, 1.3 Hz, 1H), 3.99-3.92 (m, 1H), 2.96-2.87 (m, 1H),2.81-2.75 (m, 1H). 255

HCl FF LC-MS: m/z 254.4 (MH⁺); ¹H NMR (CD₃OD): δ 7.89-7.86 (d, J = 8.61Hz, 1H), 7.76-7.76 (d, J = 1.89 Hz, 1H), 7.37-7.34 (dd, J = 8.60 Hz,1.97 Hz, 1H), 5.27-5.23 (m, 1H), 4.30-4.22 (m, 1H), 3.99-3.91 (m, 1H),3.61-3.56 (m, 1H), 3.38-3.26 (m, 1H), 3.13-2.94 (m, 2H). 256

HCl FF LC-MS: m/z 268 (MH⁺); ¹H NMR (DMSO-d₆ + D₂O): δ 7.89- 7.85 (d, J= 8.58 Hz, 1II), 7.77-7.76 (d, J = 1.38 Hz, 1H), 7.37-7.34 (dd, J = 8.80Hz, 1.70 Hz, 1H), 5.34- 5.31 (d, J = 7.77 Hz, 1H), 4.30-4.23 (m, 1H),4.01-3.94 (m, 1H), 3.66- 3.60 (m, 1H), 3.46-3.36 (m, 1H), 3.12-3.00 (m,2H), 2.80 (s, 3H). 257

HCl FF LC-MS: m/z 254 (MH⁺); ¹H NMR (CD₃OD): δ 7.69-7.66 (dd, J = 6.95Hz, 1.94 Hz, 1H), 7.47-7.40 (m, 2H), 5.30-5.26 (m, 1H), 4.32- 4.25 (m,1H), 3.40-3.92 (m, 1H), 3.64-3.60 (m, 1H), 3.42-3.35 (dd, J = 13.42 Hz,8.45 Hz, 1H), 3.10- 3.02 (m, 2H). 258

HCl FF LC-MS: m/z 268 (MH⁺); ¹H NMR (CD₃OD): 7.72-7.70 (d, J = 1.7 Hz,1H), 7.48-7.40 (m, 2H), 5.36-5.33 (m, 1H), 4.92-4.26 (m, 1H), 4.01- 3.95)m, 1H), 3.73-3.68 (m, 1H), 3.51-3.44 (m, 1H), 3.10-3.03 (m, 2H), 2.80(s, 3H). 259

HCl FF LC-MS: m/z 288 (MH⁺); ¹H NMR (CD₃OD): δ 8.12 (s, 1H), 7.92 (s,1H), 5.25-5.22 (d, J = 8.50, 1H), 4.30-4.23 (m, 1H), 3.99-3.91 (m, 1H),3.61-3.40 (m, 1H), 3.37-3.33 (m, 1H), 3.03-2.94 (m, 2H). 260

HCl FF LC-MS: m/z 302 (MH⁺); ¹H NMR (CD₃OD): δ 8.12 (s, 1H), 7.97 (s,1H), 5.33-5.29 (m, 1H), 4.31-4.24 (m, 1H), 3.99-3.92 (m, 1H), 3.71- 3.65(m, 1H), 3.48-3.41 (dd, J = 13.10 Hz, 9.17 Hz, 1H), 3.07-2.99 (m, 2H),2.80 (s, 3H). 261

HCl FF LC-MS: m/z 254 (MH⁺); ¹H NMR (CD₃OD): δ 7.88-7.85 (d, J = 8.61Hz, 1H), 7.74-7.73 (d, J = 1.65 Hz, 1H), 7.38-7.35 (dd, J = 8.57 Hz,1.79 Hz, 1H), 5.21-8.19 (m, 1H), 4.43-4.37 (m, 1H), 4.01-3.93 (m, 1H),3.53-3.46 (m, 1H), 3.33-3.23 (m, 1H), 3.04-2.93 (m, 1H), 2.88- 2.82 (m,1H). 262

HCl FF LC-MS: m/z 268 (MH⁺); ¹H NMR (CD₃OD): δ 7.90-7.87 (d, J = 8.55Hz, 1H), 7.77-7.76 (d, J = 1.98 Hz, 1H), 7.40-7.36 (dd, J = 8.58 Hz,2.04 Hz, 1H), 5.28-5.24 (m, 1H), 4.44-4.38 (m, 1H), 4.03-3.94 (m, 1H),3.62-3.56 (m, 1H), 3.43-3.35 (dd, J = 12.95 Hz, 8.42 Hz, 1H), 3.00-2.96(m, 1H), 2.90-2.79 (m, 1H), 2.79 (s, 3H). 263

HCl FF LC-MS: m/z 254 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.24 (s, 3H), 7.78-7.75 (dd, J = 7.31 Hz, 1.40 Hz, 1H), 7.54-7.46 (m, 2H), 5.21-2.19 (d, J= 6.24 Hz, 1H), 4.30-4.23 (m, 1H), 3.95-3.87 (m, 1H), 3.37 (s, 1H),3.19-3.17 (m, 1H), 2.90-2.89 (m, 2H). 264

HCl FF LC-MS: m/z 268 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.44-9.38 (m, 1H),8.93-8.86 (m, 1H), 7.80-7.75 (dd, J = 7.34 Hz, 1.43 Hz, 1H), 7.55-7.46(m, 2H), 5.34-5.32 (d, J = 7.65 Hz, 1H), 4.30-4.23 (m, 1H), 3.97-3.89(m, 1H), 3.53-3.46 (m, 1H), 3.36- 3.30 (m, 1H), 2.97-2.83 (m, 2H),2.62-2.59 (t, J = 4.80 Hz, 3H). 265

HCl FF LC-MS: m/z 288 (MH⁺); ¹H NMR (MeOD): δ 8.13 (s, 1H), 7.93 (s,1H), 5.20-5.15 (m, 1H), 4.44-4.37 (m, 1H), 4.01-3.93 (m, 1H), 3.53- 3.47(m, 1H), 3.28-3.26 (m, 1H), 3.00-2.91 (m, 1H), 2.90-2.83 (s, 1H). 266

HCl FF LC-MS: m/z 302 (MH⁺); ¹H NMR (MeOD): δ 8.14 (s, 1H), 7.94 (s,1H), 5.26-5.22 (dd, J = 8.51 Hz, 2.64 Hz, 1H), 4.43-4.38 (m, 1H),4.02-3.94 (m, 1H), 3.61-3.56 (m, 1H), 3.43-3.36 (m, 1H), 2.99-2.96 (m,1H), 2.92-2.90 (m, 1H), 2.79 (s, 3H). 267

HCl KK ¹H NMR (CD₃OD): δ 4.97 (dd, J = 2.0, 0.7 Hz, 1H), 4.05-3.99 (m,1H), 3.74-3.68 (m, 1H), 3.34-3.30 (m, 1H), 3.18 (dd, J = 3.3, 2.5 Hz,1H), 2.64-2.58 (m, 2H), 2.32 (s, 3H), 2.26 (s, 3H). 268

HCl KK ¹H NMR (CD₃OD): δ 5.03 (dd, J = 2.0, 0.7 Hz, 1H), 4.08-4.01 (m,1H), 3.74-3.67 (m, 1H), 3.39 (dd, J = 3.0, 1.0 Hz, 1H), 3.32-3.26 (m,1H), 2.75 (s, 3H), 2.69-2.61 (m 2H), 2.33 (s, 3H), 2.26 (s, 3H). 269

HCl FF ¹H NMR (CD₃OD): δ 7.87 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 2.0 Hz,1H), 7.42 (t, J = 2.0 Hz, 1H), 7.38 (t, J = 2.0 Hz, 1H), 5.19-5.15 (m,1H), 4.39 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.97 (ddd, J = 3.0, 2.5, 1.0Hz, 1H), 3.48 (dd, J = 3.3, 1.0 Hz, 1H), 3.30-3.22 (m, 1H), 3.03-2.96(m, 1H), 2.91-2.85 (m, 1H). 270

HCl FF ¹H NMR (CD₃OD): δ 7.87 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 2.0 Hz,1H), 7.42 (t, J = 2.0 Hz, 1H), 7.39 (t, J = 2.0 Hz, 1H), 5.25-5.22 (m,1H), 4.39 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.98 (ddd, J = 2.0, 1.7, 1.0Hz, 1H), 3.57 (dd, J = 3.3, 0.7 Hz, 1H), 3.38 (dd, J = 3.0, 2.0 Hz, 1H),3.05- 2.96 (m, 1H), 2.91-2.86 (m, 1H), 2.77 (s, 3H). 271

HCl FF ¹H NMR (CD₃OD): δ 7.87 (d, J = 1.7 Hz, 1H), 7.72 (d, J = 1.7 Hz,1H), 7.43 (t, J = 1.7 Hz, 1H), 7.40 (dt, J = 1.7, 0.7 Hz, 1H), 4.18-3.72(m, 2H), 3.74 (apd, J = 2.0 Hz, 1H), 3.65-3.58 (m, 2H), 3.47 (d, J = 3.0Hz, 1H), 2.93 (t, J = 1.0 Hz, 2H), 2.60-2.54 (m, 1H), 2.48-2.39 (m,1II). 272

HCl FF ¹H NMR (CD₃OD): δ 7.87 (d, J = 2.0 IIz, 1II), 7.73 (d, J = 2.0IIz, 1H), 7.42 (t, J = 2.0 Hz, 1H), 7.38 (dt, J = 2.0, 0.7 Hz, 1H),5.25-5.22 (m, 1H), 4.40 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.98 (dt, J =3.0, 1.0 Hz, 1H), 3.54 (dd, J = 3.3, 1.0 Hz, 1H), 3.36 (dd, J = 3.0, 2.0Hz,1H), 3.14 (dq, J = 1.7, 0.7 Hz, 2H), 3.00-2.96 (m, 1H), 2.91-2.87 (m,1H), 1.34 (t, J = 1.7 Hz, 3H). 273

HCl CS; FME from SFC separation of Compound 176, using isocraticIsopropanol with 0.1% Isopropylamine in CO₂ on a 4.6 × ¹H NMR (CD₃OD): δ6.87 (s, 1H), 3.41-3.35 (m, 1H), 3.33-3.25 (m, 1H), 3.05-2.96 (m, 2H),2.90-2.83 (m, 1H), 2.77-2.70 (m, 1H), 2.75 (s, 3II), 2.39-2.30 (m, 1II),2.20 (s, 3H). 100 mm ChiralPak AD- H from Chiral Technologies and flowof 4 mL/min 274

HCl CS; SME from SFC separation of Compound 176, using isocraticIsopropanol with 0.1% Isopropylamine in CO₂ on a 4.6 × ¹H NMR (CD₃OD): δ6.87 (s, 1H), 3.41-3.35 (m, 1H), 3.33-3.25 (m, 1H), 3.05-2.96 (m, 2H),2.90-2.83 (m, 1H), 2.77-2.70 (m, 1H), 2.75 (s, 3H), 2.39-2.30 (m, 1H),2.20 (s, 3H). 100 mm ChiralPak AD- H from Chiral Technologies and flowof 4 mL/min 275

HCl JJ LC-MS: m/z 218 (MH⁺); ¹H NMR (MeOD): δ 6.84 (s, 1H), 5.08-5.03(m, 1H), 4.28-4.22 (m, 1H), 3.89- 3.81 (m, 1H), 3.47-3.42 (m, 1H),3.29-3.25 (m, 1H), 2.87-2.78 (m, 1H), 2.78 (s, 3H), 2.66-2.58 (m, 1H).276

HCl GG LC-MS: m/z 246 (MH⁺); ¹H NMR (MeOD): δ 7.49-7.36 (m, 5H), 7.21(s, 1H), 5.36-5.32 (m, 1H), 4.26- 4.17 (m, 1H), 3.97-3.90 (m, 1H),3.08-3.00 (m, 1H), 2.93-2.88 (m, 1H), 2.81-2.70 (m, 2H). 277

HCl GG LC-MS: m/z 260 (MH⁺); ¹H NMR (MeOD): δ 7.50-7.38 (m, 5H), 7.24(s, 1II), 5.42-5.38 (m, 1II), 4.27-4.21 (m, 1H), 3.98-3.90 (m, 1H),2.95-2.93 (m, 1H), 2.92-2.85 (m, 2H), 2.80-2.71 (m, 1H), 2.47 (s, 3H).278

HCl GG LC-MS: m/z 247 (MH⁺); ¹H NMR CD₃OD): δ 8.90-8.88 (d, J = 6.87 Hz,2H), 8.22-8.19 (d, J = 6.87 Hz, 2H), 7.99 (s, 1H), 5.67-5.62 (m, 1H),4.31-4.24 (m, 1H), 4.03-3.91 (m, 1H), 3.22-2.85 (m, 4H). 279

HCl GG LC-MS: m/z 261 (MH⁺); ¹H NMR (MeOD): δ 8.90-8.88 (d, J = 6.87 Hz,2H), 8.22-8.19 (d, J = 6.87 Hz, 2H), 7.99 (s, 1H), 5.74-5.71 (m, 1H),4.31-4.24 (m, 1H), 4.03-3.95 (m, 1H), 3.32-2.94 (m, 4H), 2.61 (s, 3H).280

HCl FF LC-MS: m/z 288 (MH⁺); ¹H NMR (MeOD): δ 7.85-7.82 (d, J = 8.40 Hz,1H), 7.51-7.49 (d, J = 8.40 Hz, 1H), 5.76-5.73 (d, J = 9.92 Hz, 1H),4.24-4.16 (m, 1H), 4.09-4.00 (m, 1H), 3.67-3.61 (m, 1H), 3.41-3.35 (m,1H), 3.12-2.99 (m, 2H). 281

HCl FF LC-MS: m/z 302 (MH⁺); ¹H NMR (D₂O): δ 7.42-7.41 (d, J = 2.42 Hz,1H), 7.15 (s, 1H), 5.50 (s, 1H), 4.00 (s, 2H), 3.45 (s, 2H), 2.98-2.85(m, 2H), 2.70 (s, 3H). 282

HCl B LC-MS: m/z 184 (MH⁺); ¹H NMR (MeOD): δ 7.28 (d, J = 1.3 Hz, 1H),6.85 (d, J = 1.3 Hz, 1H), 5.00-4.96 (m, 1H), 4.24 (ddd, J = 2.8, 1.4,0.3 Hz, 1H), 3.75 (dt, J = 2.8, 1.0 Hz, 1H), 3.10 (t, J = 1.7 Hz, 2H),2.90- 2.81 (m, 1H), 2.64-2.59 (m, 1H), 2.30-2.22 (m, 1H), 2.09-2.00 (m,1H). 283

HCl B LC-MS: m/z 198 (MH⁺); ¹H NMR (MeOD): δ 7.29 (d, J = 1.3 Hz, 1H),6.86 (d, J = 1.3 Hz, 1H), 5.00-4.97 (m, 1H), 4.25 (ddd, J = 2.9, 1.5,0.4 Hz, 1H), 3.75 (dt, J = 2.9, 0.9 Hz, 1H), 3.23-3.12 (m, 2H),2.90-2.81 (m, 1H), 2.69 (s, 3H), 2.64-2.59 (m, 1H), 2.33-2.25 (m, 1H),2.12-2.02 (m, 1H). 284

HCl CS; FME from SFC separation of Compound 178, using isocratic 7%Hexane: Isopropanol (7:3) in CO₂ on ¹H NMR (CD₃OD): δ 7.35 (d, J = 1.3Hz, 1II), 6.85 (d, J = 1.3 Hz, 1H), 3.62-3.55 (m, 1H), 3.33-3.24 (m,1H), 3.11-3.05 (m, 1H), 2.90- 2.80 (m, 1H), 2.79-2.65 (m, 2H), 2.75 (s,3H), 2.33-2.25 (m, 1H). a 4.6 × 100 mm (S,S) Whelk0-1 from Regis andflow of 4 mL/min 285

HCl CS; SME from SFC separation of Compound 178, using isocratic 7%Hexane: Isopropanol (7:3) in CO₂ on ¹H NMR (CD₃OD): δ 7.35 (d, J = 1.3Hz, 1H), 6.85 (d, J = 1.3 Hz, 1H), 3.62-3.55 (m, 1H), 3.33-3.24 (m, 1H),3.11-3.05 (m, 1H), 2.90- 2.80 (m, 1H), 2.79-2.65 (m, 2H), 2.75 (s, 3H),2.33-2.25 (m, 1H). a 4.6 × 100 mm (S,S) Whelk0-1 from Regis and flow of4 mL/min 286

HCl F ¹H NMR (CD₃OD): δ 7.30 (d, J = 1.3 Hz, 1H), 6.91 (d, J = 1.3 Hz,1H), 5.23 (apd, J = 2.3 Hz, 1H), 4.29 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H),3.88-3.77 (m, 2H), 3.76-3.46 (m, 6H), 3.43-3.29 (m, 2H), 3.25-3.20 (m,1H), 3.05-2.98 (m, 1H), 2.85- 2.80 (m, 1H). 287

HCl B ¹H NMR (CD₃OD): δ 7.37 (d, J = 1.3 Hz, 1H), 6.91 (d, J = 1.3 Hz,1H), 5.40-5.33 (m, 1H), 4.82-4.25 (m, 2H), 3.85 (dt, J = 2.5, 1.0 Hz,1H), 3.88-3.75 (m, 6H), 3.54-3.44 (m, 1H), 3.28-3.12 (m, 2H), 2.91- 2.83(m, 1H), 2.74-2.67 (m, 1H). 288

HCl F ¹H NMR (CD₃OD): δ 7.29 (d, J = 0.7 Hz, 1H), 6.91 (d, J = 0.7 Hz,1H), 5.18 (d, J = 2.0 Hz, 1H), 4.27 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H),3.87- 3.78 (m, 2H), 3.77-3.40 (m, 6H), 3.39-3.12 (m, 3H), 3.11-2.87 (m,1H), 2.99 (s, 3H), 2.92-2.82 (m, 1H). 289

HCl B ¹H NMR (CD₃OD): δ 7.35 (d, J = 1.3 Hz, 1H), 6.90 (d, J = 1.3 Hz,1H), 5.29 (brd, J = 2.3 Hz, 1H), 4.26 (ddd, J = 3.0, 1.3, 0.7 Hz, 1H),3.83 (dt, J = 2.0, 1.0 Hz, 1H), 3.80-3.32 (m, 9H), 3.25 (m, 1H), 3.00(s, 3H), 2.89-2.82 (m, 1H), 2.72-2.65 (m, 1H). 290

HCl W LC-MS: m/z 183 (MH⁺); ¹H NMR (CD₃OD): δ 3.47-3.42 (m, 2H),3.21-3.09 (m, 1H), 2.99 (s, 3H), 2.88 (s, 2H), 2.35-2.14 (m, 2H),1.97-1.92 (m, 2H). 291

HCl W LC-MS: m/z 197 (MH⁺); ¹H NMR (CD₃OD): δ 3.21 (s, 1H), 3.04- 2.94(m, 1H), 2.91-2.87 (m, 1H), 2.73-2.64 (m, 2H), 2.61 (s, 3H), 2.59 (s,3H), 2.12-1.99 (m, 2H), 1.84-1.79 (m, 2H), 1.72-1.64 (m, 1H). 292

HCl FF LC-MS: m/z 288 (MH⁺); ¹H NMR (CD₃OD): δ 7.86-7.83 (d, J = 8.61Hz, 1H), 7.52-7.49 (d, J = 8.58 Hz, 1H), 5.76-5.73 (d, J = 9.90 Hz, 1H),4.24-4.17 (m, 1H), 4.07-4.00 (m, 1H), 3.66-3.62 (d, J = 11.19 Hz, 1H),3.42-3.38(d, J = 9.48 Hz, 1H), 3.17-3.00 (m, 2H). 293

HCl FF LC-MS: m/z 302 (MH⁺); ¹H NMR (CD₃OD): δ 7.85-7.82 (d, J = 8.55,1H), 7.51-7.49 (d, J = 8.58, 1H), 5.84-5.81 (d, J = 9.55, 1H), 4.25-4.19 (m, 1H), 4.08-4.01 (m, 1H), 3.72-3.67 (dd, J = 13.43 Hz, 2.48 Hz,1H), 3.54-3.47 (m, 1H), 3.12- 3.05 (m, 2H), 2.81 (s, 3H). 294

HCl CS; FME from SFC separation of Boc- protected Compound 9, usingisocratic 10% MeOH in CO₂ on a 4.6 × ¹H NMR (DMSO-d⁶): δ 8.22 (br s,3H), 6.70 (s, 1H), 4.85-4.83 (d, J = 8.01 Hz, 1H), 4.13-4.07 (m, 1H),3.78-3.70 (m, 1H), 3.29 (s, 1H), 2.91-2.67 (m 5H), 1.22-1.18 (t, J =7.50 IIz, 3II). 100 mm LUX Cellulose 2 from Phenomenex and flow of 4mL/min 295

HCl CS; SME from SFC separation of Boc- protected Compound 9, usingisocratic 10% MeOH in CO₂ on a 4.6 × ¹H NMR (DMSO-d⁶): δ 8.22 (br s,3H), 6.70 (s, 1H), 4.85-4.83 (d, J = 8.01 Hz, 1H), 4.13-4.07 (m, 1H),3.78-3.70 (m, 1H), 3.29 (s, 1H), 2.91-2.67 (m, 5H), 1.22-1.18 (t, J =7.50 Hz, 3H). 100 mm LUX Cellulose 2 from Phenomenex and flow of 4mL/min 296

HCl X LC-MS: m/z 183 (MH⁺); ¹H NMR (CD₃OD): δ 3.46-3.35 (m, 2H),3.25-3.19 (m, 1H), 2.93 (s, 3H), 2.89-2.85 (t, J = 5.43 Hz, 2H), 2.12-2.01 (m, 2H), 1.96-1.85 (m, 2H). 297

HCl X LC-MS: m/z 197 (MH⁺); ¹H NMR (CD₃OD): δ 3.51-3.33 (m, 3H), 2.94(s, 3H), 2.89-2.85 (m, 2H), 2.83 (s, 3H), 2.13-1.90 (m, 4H). 298

HCl Q LC-MS: m/z 196 (MH⁺); ¹H NMR (CD₃OD): δ 6.88 (s, 1H), 3.47- 3.38(m, 1H), 3.27-3.26 (m, 1H), 3.18-3.09 (m, 2H), 3.06-2.97 (m, 2H),2.93-2.83 (m, 1H), 2.80-2.68 (m, 1H), 2.47-2.38 (m, 1H), 8.24- 2.22 (m,3H), 1.39-1.36 (t, J = 7.29 Hz, 3H). 299

HCl HH LC-MS: m/z 202 (MH⁺); ¹H NMR (CD₃OD): δ 6.89 (s, 1H), 3.45-3.40(m, 1H), 3.31-3.29 (m, 1H), 3.09- 2.94 (m, 3H), 2.74-2.65 (m, 4H),2.28-2.17 (m, 1H). 300

HCl Q LC-MS: m/z 196 (MH⁺); ¹H NMR (CD₃OD): δ 6.93 (s, 1H), 3.45- 3.39(m, 1H), 3.28-3.24 (m, 1H), 3.08-2.98 (m, 2H), 2.94-2.89 (m, 1II),2.74-2.68 (m, 4II), 2.64-2.56 (m, 2H), 2.42-2.32 (m, 1H), 1.29- 1.24 (t,J = 7.52 Hz, 3H). 301

HCl Q LC-MS: m/z 196 (MH⁺); ¹H NMR (CD₃OD): δ 3.39 (m, 1H), 3.28-3.23(m, 1H), 3.02-2.93 (m, 2H), 2.87-2.78 (m, 1H), 2.76 (s, 3H), 2.71-2.61(m, 1H), 2.35-2.22 (m, 1H), 2.31 (s, 3H), 2.10 (s, 3H). 302

HCl Q LC-MS: m/z 236 (MH⁺); ¹H NMR (CD₃OD): δ 6.89 (s, 1H), 3.78- 3.75(m, 1H), 3.58-3.52 (m, 2H), 3.21-3.00 (m, 4H), 2.94-2.72 (m, 3H),2.50-2.41 (m, 1H), 2.23-2.22 (d, J = 0.96 Hz, 3II), 2.02-1.81 (m, 5H),1.59 (s, 1H). 303

HCl A LC-MS: m/z 310 (MH⁺); ¹H NMR (CD₃OD): δ 7.98-7.75 (m, 2H),7.72-7.66 (m, 3H), 7.50-7.45 (t, J = 7.47 Hz, 2H), 7.40-7.37 (m, 1H),5.29-5.26 (m, 1H), 4.47-4.41 (m, 1H), 4.06-4.00 (m, 1H), 3.63-3.58 (m,1H), 3.45-3.38 (m, 1H), 3.63- 3.38 (m, 2H)), 2.80 (s, 3H). 304

HCl FF LC-MS: m/z 296 (MH⁺); ¹H NMR (CD₃OD): δ 7.97-7.94 (d, J = 8.34Hz, 1H), 7.88-7.87 (d, J = 1.26 Hz, 1H), 7.73-7.70 (m, 2H), 7.65-7.62(dd, J = 8.37 Hz, 1.65 Hz, 1H), 7.51-7.48 (t, J = 7.47 Hz, 2H), 7.40-7.35 (m, 1H), 5.37-5.34 (d, J = 8.52 Hz, 1H), 4.81-4.25 (m, 1H), 4.02-3.94 (m, 1H), 3.70-3.64 (m, 1H), 3.42-3.37 (m, 1H), 3.32-3.01 (m, 2H).305

HCl FF LC-MS: m/z 310 (MH⁺); ¹H NMR (CD₃OD): δ 7.96-7.91 (m, 2H),7.74-7.71 (d, J = 7.11 Hz, 2H), 7.65-7.62 (dd, J = 8.40 Hz, 1.68 Hz,1H), 7.50-7.48 (t, J = 7.47 Hz, 2H), 7.40-7.37 (m, 1H), 5.43-5.40 (d, J= 6.24 Hz, 1H), 4.84-4.28 (m, 1H), 4.02-3.96 (m, 1H), 3.77-3.72 (dd, J =13.07 Hz, J = 2.60 Hz, 1H), 3.53- 3.33 (m, 1H), 3.32-3.03 (m, 2H), 2.80(s, 3H). 306

HCl II LC-MS: m/z 280 (MH⁺); ¹H NMR (CD₃OD): δ 7.87-7.84 (d, J = 8.34Hz, 2H), 7.58-7.57 (d, J = 1.80 Hz, 3H), 7.39-7.34 (m, 2H), 7.28-7.24(m, 1H), 4.63-4.60 (m, 1H), 2.97- 2.88 (m, 2H), 2.30-2.21 (m, 1H),2.08-1.94 (m, 3H). 307

HCl II LC-MS: m/z 294 (MH⁺); ¹H NMR (DMSO-d₆): δ 7.99-7.97 (m, 2H),7.74-7.69 (m, 3H), 7.51-7.46 (t, J = 7.49 Hz, 2H), 7.40-7.38 (m, 1H),4.67-4.65 (m, 1H), 2.89 (s, 3H), 2.35-2.29 (m, 1H), 2.23-2.18 (m, 1H),2.13-2.03 (m, 2H), 1.61 (s, 2H). 308

2HCl X LC-MS: m/z 212 (MH⁺); ¹H NMR (CD₃OD): δ 3.49-3.43 (m, 1H),3.31-3.28 (m, 2H), 3.16 (s, 3H), 2.81 (s, 3H), 2.62-2.61 (m, 2H),1.96-1.74 (m, 4H). 309

formate B LC-MS: m/z 198 (MH⁺); ¹H NMR (CD₃OD): δ 7.33 (d, J = 1.2, 0.7Hz, 1H), 7.15 (brs, 1H), 7.04 (dd, J = 1.2, 0.3 Hz, 1H), 4.82 (t, J =1.2 Hz, 1H), 4.00-3.94 (m, 1H), 3.88- 3.82 (m, 1H), 3.25 (d, J = 1.2 Hz,2H), 2.96 (t, J = 1.6 Hz, 2H), 2.85 (s, 6H). 310

HCl CS; FMB from SFC separation of Compound 13, using isocratic 10%Hx:MeOH:EtOH (2:1:1) in CO₂ on a 4.6 × 100 mm LUX Cellulose 2 from GC-MSm/z 139 (M⁺); ¹H NMR (DMSO-d⁶): δ 9.02 (s, 1H), 8.65 (s, 1H), 7.41-7.40(d, J = 5.19 Hz, 1H), 6.99-6.97 (d, J = 5.19 Hz, 1H), 5.03-5.00 (d, J =8.13 Hz, 1H), 4.21-4.12 (m, 1H), 3.83-3.75 (m, 1H), 3.52-3.48 (d, J =12.43 Hz, 1H), 3.13-2.72 (m, 5H), 1.25-1.20 (t, J = 7.26 Hz, 3H).Phenomenex and flow of 4 mL/min 311

IICl CS; SME from SFC separation of Compound 13, using isocratic 10%Hx:MeOH:EtOH (2:1:1) in CO₂ on a 4.6 × 100 mm LUX Cellulose 2 from GC-MSm/z 139 (M⁺); ¹H NMR (DMSO-d⁶): δ 9.02 (s, 1H), 8.65 (s, 1H), 7.41-7.40(d, J = 5.19 Hz, 1H), 6.99-6.97 (d, J = 5.19 Hz, 1H), 5.03-5.00 (d, J =8.13 Hz, 1H), 4.21-4.12 (m, 1H), 3.83-3.75 (m, 1H), 3.52-3.48 (d, J =12.43 Hz, 1H), 3.13-2.72 (m, 5H), 1.25-1.20 (t, J = 7.26 Hz, 3H).Phenomenex and flow of 4 mL/min *FB is an abbreviation for “free base”.

D. Animal Models

Anti-psychotic like activity of the compounds was evaluated in miceusing the PCP hyperactivity and Pre-Pulse Inhibition (PPI) models ofschizophrenia.

1. Methods

Animals: Male C57Bl/6J mice from Jackson Laboratories (Bar Harbor, Me.)were used. Upon receipt, mice were assigned unique identificationnumbers (tail marked) and were group housed with 4 mice per cage inOptiMICE ventilated cages. All animals remained housed in groups of fourduring the remainder of the study. All mice were acclimated to thecolony room for at least two weeks prior to testing. During the periodof acclimation, mice were examined on a regular basis, handled, andweighed to assure adequate health and suitability. Animals weremaintained on a 12/12 light/dark cycle. The room temperature wasmaintained between 20 and 23° C. with a relative humidity maintainedbetween 30% and 70%. Chow and water were provided ad libitum for theduration of the study. In each test, animals were randomly assignedacross treatment groups.

2. PCP Hyperactivity

Open field (OF) chambers were Plexiglas square chambers (27.3×27.3×20.3cm; Med Associates Inc., St Albans, Vt.) surrounded by infraredphotobeams (16×16×16) to measure horizontal and vertical activity. Theanalysis was configured to divide the open field into a center andperiphery zone. Distance traveled was measured from horizontal beambreaks as the mouse moved whereas rearing activity was measured fromvertical beam breaks.

Mice were injected with vehicle, test compound, or clozapine (1mg/kg;i.p) and placed in the OF chambers for 30 min measurement ofbaseline activity. Mice were then injected with either water or PCP (5mg/kg;i.p) and placed back in the OF chambers for a 60-minute session.At the end of each OF test session the OF chambers were thoroughlycleaned.

3. Prepulse Inhibition of Startle

The acoustic startle is an unconditioned reflex response to an externalauditory stimulus. Prepulse inhibition of startle (PPI) refers to thereduction in the startle response caused by the presentation of alow-intensity auditory stimulus prior to the startle stimulus. The PPIparadigm is used for the study of schizophrenia and antipsychotic actiondue to the similarities between the results from human and rodentstudies. PPI has been used as a tool for the assessment of deficienciesin sensory-motor gating observed in schizophrenia and to screen forpotential antipsychotic drugs. Various psychotomimetic drugs such as PCPcan disrupt PPI. In mice, antipsychotic drugs such as clozapine canreverse the disruption of PPI induced by PCP.

Mice were placed in the PPI chambers (Med Associates) for a 5 minsession of white noise (70 dB) habituation. After the habituation periodthe test session was initiated. The session started with a habituationblock of 6 presentations of the startle stimulus alone, followed by 10PPI blocks, each of which consisted of 6 different types of trials.Trial types were: ‘null’ (no stimuli), ‘startle’ (120 dB), ‘startle plusprepulse’ (4, 8 and 12 dB over background noise, i.e., 74, 78 or 82 dB)and ‘prepulse’ (82 dB). Trial types were presented in a random orderwithin each block. Each trial started with a 50 ms stimulus-free periodduring which baseline movements were recorded. This was followed by asubsequent 20 ms period during which the prepulse stimulus was presentedand responses to the prepulse measured. After a further 100 ms period,the startle stimulus was presented for 40 ms and responses recorded for100 ms from startle onset. Responses were sampled every ms. Theinter-trial interval was variable with an average of 15 s (range from 10to 20 s). In ‘startle’ trials the basic auditory startle response wasmeasured. The basic startle response was calculated as the mean startleresponse of all ‘startle’ trials (i.e., excluding the first habituationblock). In ‘startle plus prepulse’ trials the degree of inhibition ofthe normal startle was calculated and expressed as a percentage of thebasic startle response.

Mice were treated with vehicle, haloperidol (1 mg/kg:i.p) or testcompound 30 min prior to PPI test. The PPI enclosures were cleanedfollowing each test.

4. Results

TABLE 1 Effects of Compounds on Pre-pulse Inhibition (PPI) in MiceCompound/Doses Effect Compound 5 10 mg/kg − 30 mg/kg +++ 100 mg/kg  +++Compound 58 10 mg/kg +++ 30 mg/kg + 100 mg/kg  +++ Compound 57 10 mg/kg− 30 mg/kg − 100 mg/kg  ++ Compound 4 10 mg/kg +++ 30 mg/kg − 100 mg/kg +++ Compound 27 10 mg/kg − 30 mg/kg − 100 mg/kg  − Compound 28 10 mg/kg− 30 mg/kg +++ 100 mg/kg  +++ Compound 1 10 mg/kg − 30 mg/kg +++ 100mg/kg  +++ Compound 2 10 mg/kg − 30 mg/kg − 100 mg/kg  +++ Compound 3 10mg/kg +++ 30 mg/kg +++ 100 mg/kg  − Compound 10 10 mg/kg +++ 30 mg/kg+++ 100 mg/kg  +++ Compound 75 10 mg/kg − 30 mg/kg − 100 mg/kg  −Compound 76 10 mg/kg − 30 mg/kg − 100 mg/kg  − Compound 13 10 mg/kg − 30mg/kg − 100 mg/kg  +++ Compound 140 10 mg/kg − 30 mg/kg − 100 mg/kg  −Compound 78 10 mg/kg − 30 mg/kg − 100 mg/kg  − Compound 158  3 mg/kg −10 mg/kg − 30 mg/kg − 100 mg/kg  +++ Compound 130  3 mg/kg − 10 mg/kg −30 mg/kg − Compound 131  3 mg/kg − 10 mg/kg − 30 mg/kg − Compound 171  3mg/kg − 10 mg/kg − 30 mg/kg − 100 mg/kg  +++ Compound 172  3 mg/kg − 10mg/kg − 30 mg/kg − 100 mg/kg  − Compound 129  3 mg/kg +++ 10 mg/kg +++30 mg/kg +++ Compound 310  3 mg/kg − 10 mg/kg − 30 mg/kg +++ Compound205  3 mg/kg − 10 mg/kg − 30 mg/kg +++ Compound 311  3 mg/kg − 10 mg/kg− 30 mg/kg +++ Compound 213  3 mg/kg − 10 mg/kg +++ 30 mg/kg +++Compound 170  3 mg/kg − 10 mg/kg +++ 30 mg/kg +++ Compound 242  3 mg/kg− 10 mg/kg − 30 mg/kg − Compound 127  3 mg/kg +++ 10 mg/kg − 30 mg/kg+++ Compound 102  3 mg/kg − 10 mg/kg − 30 mg/kg − *P < 0.05 vs. vehicle−: No change in PPI +: Significant increase in PPI at one pre-pulseintensity (P value < 0.05) ++: Significant increase in PPI at twopre-pulse intensities (P value < 0.05) +++: Significant increase in PPIat three pre-pulse intensities (P value < 0.05)

TABLE 2 Effects of Compounds on PCP-Induced Hyperactivity Responses inMice Compound/Doses Total Distance Traveled (cm) Compound 4 0.3 mg/kgCompound + PCP  +  1 mg/kg Compound + PCP +  3 mg/kg Compound + PCP + 10mg/kg Compound + PCP + 30 mg/kg Compound + PCP + 100 mg/kg Compound +PCP  + Compound 27 0.3 mg/kg Compound + PCP  −  1 mg/kg Compound + PCP − 3 mg/kg Compound + PCP − 10 mg/kg Compound + PCP + 30 mg/kg Compound +PCP + 100 mg/kg Compound + PCP  + Compound 28 0.3 mg/kg Compound +PCP  +  1 mg/kg Compound + PCP +  3 mg/kg Compound + PCP + 10 mg/kgCompound + PCP + 30 mg/kg Compound + PCP + 100 mg/kg Compound + PCP  +Compound 2 10 mg/kg Compound + PCP + 30 mg/kg Compound + PCP + 100 mg/kgCompound + PCP  − Compound 3 10 mg/kg Compound + PCP − 30 mg/kgCompound + PCP − 100 mg/kg Compound + PCP  − Compound 1 10 mg/kgCompound + PCP + 30 mg/kg Compound + PCP + 100 mg/kg Compound + PCP  −Compound 5 10 mg/kg Compound + PCP + 30 mg/kg Compound + PCP + 100 mg/kgCompound + PCP  + Compound 57 10 mg/kg Compound + PCP + 30 mg/kgCompound + PCP + 100 mg/kg Compound + PCP  + Compound 58 10 mg/kgCompound + PCP + 30 mg/kg Compound + PCP + 100 mg/kg Compound + PCP  +Compound 10 10 mg/kg Compound + PCP + 30 mg/kg Compound + PCP + 100mg/kg Compound + PCP  + Compound 75 10 mg/kg Compound + PCP + 30 mg/kgCompound + PCP − 100 mg/kg Compound + PCP  + Compound 76 10 mg/kgCompound + PCP − 30 mg/kg Compound + PCP − 100 mg/kg Compound + PCP  +Compound 140 10 mg/kg Compound + PCP − 30 mg/kg Compound + PCP − 100mg/kg Compound + PCP  + Compound 78 10 mg/kg Compound + PCP + 30 mg/kgCompound + PCP + 100 mg/kg Compound + PCP  + Compound 129 0.3 mg/kgCompound + PCP  +  1 mg/kg Compound + PCP +  3 mg/kg Compound + PCP + 10mg/kg Compound + PCP + 30 mg/kg Compound + PCP + 100 mg/kg Compound +PCP  + Compound 130 0.3 mg/kg Compound + PCP  −  1 mg/kg Compound + PCP−  3 mg/kg Compound + PCP + 10 mg/kg Compound + PCP + 30 mg/kgCompound + PCP + 100 mg/kg Compound + PCP  + Compound 119 10 mg/kgCompound + PCP + 30 mg/kg Compound + PCP + 100 mg/kg Compound + PCP  +Compound 158  1 mg/kg Compound + PCP +  3 mg/kg Compound + PCP + 10mg/kg Compound + PCP + 30 mg/kg Compound + PCP + 100 mg/kg Compound +PCP  + Compound 131 0.3 mg/kg Compound + PCP  −  1 mg/kg Compound +PCP +  3 mg/kg Compound + PCP + Compound 171 0.3 mg/kg Compound + PCP  − 1 mg/kg Compound + PCP −  3 mg/kg Compound + PCP − 10 mg/kg Compound +PCP − 30 mg/kg Compound + PCP + Compound 172 0.3 mg/kg Compound + PCP  − 1 mg/kg Compound + PCP +  3 mg/kg Compound + PCP + 10 mg/kg Compound +PCP − 30 mg/kg Compound + PCP − Compound 127 0.3 mg/kg Compound + PCP  − 1 mg/kg Compound + PCP −  3 mg/kg Compound + PCP + 10 mg/kg Compound +PCP + 30 mg/kg Compound + PCP − Compound 310 0.3 mg/kg Compound + PCP  + 1 mg/kg Compound + PCP −  3 mg/kg Compound + PCP − 10 mg/kg Compound +PCP + 30 mg/kg Compound + PCP + Compound 311 0.3 mg/kg Compound + PCP  − 1 mg/kg Compound + PCP +  3 mg/kg Compound + PCP + 10 mg/kg Compound +PCP + 30 mg/kg Compound + PCP + Compound 205 0.3 mg/kg Compound + PCP  + 1 mg/kg Compound + PCP +  3 mg/kg Compound + PCP + 10 mg/kg Compound +PCP + 30 mg/kg Compound + PCP + Compound 213 0.3 mg/kg Compound + PCP  + 1 mg/kg Compound + PCP +  3 mg/kg Compound + PCP + 10 mg/kg Compound +PCP + 30 mg/kg Compound + PCP + Compound 170 0.3 mg/kg Compound + PCP  − 1 mg/kg Compound + PCP −  3 mg/kg Compound + PCP − 10 mg/kg Compound +PCP − 30 mg/kg Compound + PCP − Compound 242 0.3 mg/kg Compound + PCP  − 1 mg/kg Compound + PCP +  3 mg/kg Compound + PCP + 10 mg/kg Compound +PCP + 30 mg/kg Compound + PCP + Compound 102 0.3 mg/kg Compound + PCP  − 1 mg/kg Compound + PCP +  3 mg/kg Compound + PCP + 10 mg/kg Compound +PCP + 30 mg/kg Compound + PCP + *P < 0.05 vs. vehicle + PCP −: Noinhibition of PCP hyperactivity +: Significant inhibition of PCPhyperactivity (P value < 0.05)

The embodiments described above are intended to be merely exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the disclosure and are encompassedby the appended claims.

All of the patents, patent applications and publications referred toherein are incorporated by reference herein in their entireties.Citation or identification of any reference in this application is notan admission that such reference is available as prior art to thisapplication. The full scope of the disclosure is better understood withreference to the appended claims.

What is claimed is: 1-39. (canceled)
 40. A compound of formula (Ma):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR¹ and R² are each independently (i) hydrogen, alkyl, alkoxyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, oraralkyl, each of which is optionally substituted; or (ii) —(CH₂)_(p)—R⁸,wherein R⁸ is SO₂alkyl or SO₂aryl, each of which is optionallysubstituted; or (iii) R¹ and R² together with the nitrogen atom to whichthey are attached form an optionally substituted heterocyclyl orheteroaryl; R³ and R⁴ are each independently (i) hydrogen, alkyl,alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl, or aralkyl, each of which is optionally substituted; or (ii)—(CH₂)_(p)—R⁹, wherein R⁹ is CF₃, CN, nitro, amino, hydroxyl, orcycloalkoxyl, each of which is optionally substituted; or (iii) R³ andR⁴ together with the carbon atom to which they are attached form anoptionally substituted cycloalkyl or heterocyclyl; or (iv) R³ and R¹together with the atoms to which they are attached form an optionallysubstituted heterocyclyl, and R⁴ is (i) or (ii); or (v) R³ and R⁴ arecombined together to form a double bond and together with R¹ and/or R²and the atoms to which they are attached form an optionally substitutedheteroaryl; R⁵ is (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which isoptionally substituted; or (ii) —(CH₂)_(p)—R¹⁰, wherein R¹⁰ is CF₃, CN,nitro, amino, hydroxyl, or cycloalkoxyl, each of which is optionallysubstituted; or (iii) R⁵ and R¹ together with the atoms to which theyare attached form an optionally substituted heterocyclyl; R⁶ and R⁷ areeach independently (i) hydrogen, halo, alkyl, alkoxyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each ofwhich is optionally substituted; or (ii) —(CH₂)_(p)—R¹¹, wherein R¹¹ isCF₃, CN, nitro, amino (—NH₂), hydroxyl, cycloalkoxyl, heteroaryl, orheterocyclyl, each of which is optionally substituted; or (iii) R⁶ andR⁷ together with the atoms to which they are attached form an optionallysubstituted aryl, heteroaryl, cycloalkyl or heterocyclyl ring; m is 0,1, or 2; n is 0, 1, or 2; and each occurrence of p is independently 0,1, or
 2. 41. The compound of claim 40, or a pharmaceutically acceptablesalt or stereoisomer thereof, wherein R⁵ is H.
 42. The compound of claim40, or a pharmaceutically acceptable salt or stereoisomer thereof,wherein n is
 1. 43. The compound of claim 40, or a pharmaceuticallyacceptable salt or stereoisomer thereof, wherein m is
 0. 44. Thecompound of claim 40, or a pharmaceutically acceptable salt orstereoisomer thereof, wherein R¹ and R² are each independently hydrogen,alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, or aralkyl, each of which is optionallysubstituted.
 45. The compound of claim 44, or a pharmaceuticallyacceptable salt or stereoisomer thereof, wherein the alkyl, alkoxyl,aminoalkyl, alkenyl, alkynyl, and cycloalkyl are optionally substitutedwith one or more halo.
 46. The compound of claim 44, or apharmaceutically acceptable salt or stereoisomer thereof, wherein R¹ andR² are each independently hydrogen or alkyl.
 47. The compound of claim40, or a pharmaceutically acceptable salt or stereoisomer thereof,wherein R³ and R⁴ are each independently hydrogen or alkyl.
 48. Thecompound of claim 40, or a pharmaceutically acceptable salt orstereoisomer thereof, wherein R⁶ and R⁷ are each independently hydrogen,halo, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, or aralkyl, each of which is optionallysubstituted.
 49. The compound of claim 48, or a pharmaceuticallyacceptable salt or stereoisomer thereof, wherein R⁶ and R⁷ are eachindependently hydrogen, halo, or alkyl.
 50. The compound of claim 40,wherein R¹, R², R⁶, and R⁷ are each independently hydrogen or optionallysubstituted C₁-C₄ alkyl.
 51. The compound of claim 50, wherein R¹, R²,R⁶, and R⁷ are each independently hydrogen or unsubstituted methyl orethyl.
 52. The compound of claim 47, wherein R¹, R², R⁶, and R⁷ are eachindependently hydrogen or optionally substituted C₁-C₄ alkyl.
 53. Thecompound of claim 40, wherein the compound is:

or a pharmaceutically acceptable salt or stereoisomer thereof.
 54. Acompound, wherein the compound is:

or a pharmaceutically acceptable salt or stereoisomer thereof.
 55. Thecompound of claim 40, wherein the compound is:

or a pharmaceutically acceptable salt or stereoisomer thereof.
 56. Apharmaceutical composition comprising a compound of claim 40, or apharmaceutically acceptable salt or stereoisomer thereof, and apharmaceutically acceptable excipient or carrier.
 57. A method oftreating neurological disorder, comprising administering to a subject atherapeutically effective amount of a compound of claim 40, or apharmaceutically acceptable salt or stereoisomer thereof.
 58. The methodof claim 57, wherein the neurological disorder is schizophrenia,schizophrenia spectrum disorder, acute schizophrenia, chronicschizophrenia, NOS schizophrenia, schizoid personality disorder,schizotypal personality disorder, delusional disorder, psychosis,psychotic disorder, brief psychotic disorder, shared psychotic disorder,psychotic disorder due to a general medical condition, drug-inducedpsychosis, psychoaffective disorder, aggression, delirium, Parkinson'spsychosis, excitative psychosis, Tourette's syndrome, organic or NOSpsychosis, seizure, agitation, post-traumatic stress disorder, behaviordisorder, neurodegenerative disease, Alzheimer's disease, Parkinson'sdisease, dyskinesias, Huntington's disease, dementia, mood disorder,anxiety, affective disorder, depression, major depressive disorder,dysthymia, bipolar disorder, manic disorder; seasonal affectivedisorder; attention deficit disorder, attention deficit hyperactivitydisorder, obsessive-compulsive disorder, vertigo, epilepsy, pain,neuropathic pain, sensitization accompanying neuropathic pain,inflammatory pain, fibromyalgia, migraine, cognitive impairment,movement disorder, restless leg syndrome, multiple sclerosis, sleepdisorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jetlag, drowsy side effect of medications, insomnia, substance abuse ordependency, addiction, eating disorder, sexual dysfunction,hypertension, emesis, Lesche-Nyhane disease, Wilson's disease, autism,Huntington's chorea, or premenstrual dysphoria.
 59. A method ofpreparing a compound of formula (IIIa):

or a pharmaceutically acceptable salt or stereoisomer thereof, themethod comprising: (a) treating a hydroxyalkyl thiophene of formula (i):

with an amino-aldehyde acetal and an acid, to produce a compound offormula (IIIa), wherein: m is 0; n is 1; R¹ and R² are eachindependently hydrogen or C₁-C₄ alkyl; R³ and R⁴ are each independentlyhydrogen or C₁-C₄ alkyl; R⁵ is hydrogen; and R⁶ and R⁷ are eachindependently hydrogen, halo, or C₁-C₄ alkyl.
 60. The method accordingto claim 59, wherein the acid is trifluoromethyl sulfonic acid.
 61. Themethod according to claim 59, wherein R¹ is hydrogen or C₁-C₄ alkyl andR² is hydrogen.
 62. The method according to claim 59, wherein R³ and R⁴are hydrogen.
 63. The method according to claim 59, wherein theamino-aldehyde acetal is an amino-aldehyde dimethyl acetal of formula(ii):

wherein: m is 0; n is 1; R¹ and R² are each independently hydrogen orC₁-C₄ alkyl; R³ and R⁴ are each independently hydrogen or C₁-C₄ alkyl;and R⁵ is hydrogen.
 64. The method according to claim 59, wherein theamino-aldehyde acetal comprises an amino-aldehyde diethyl acetal. 65.The method of claim 59, wherein the compound of formula (IIIa) or apharmaceutically acceptable salt or stereoisomer thereof is selectedfrom the following compounds or pharmaceutically acceptable salts orstereoisomers thereof:


66. The method according to claim 59, wherein the compound of formula(IIIa) or a pharmaceutically acceptable salt or stereoisomer thereof is:

or a pharmaceutically acceptable salt or stereoisomer thereof.
 67. Themethod of claim 59, comprising combining2-(2-bromothiophen-3-yl)ethanol, aminoacetaldehyde diethyl acetal,1,4-dioxane, and triflic acid, and isolating said compound, to obtain

or a pharmaceutically acceptable salt or stereoisomer thereof.
 68. Acompound of formula

or a pharmaceutically acceptable salt or stereoisomer thereof, preparedby the method of claim 59.